Mendelian analysis

The Mendelian analysis dialog reports variants in a single index case that meet minimum filtering criteria and follow a Mendelian inheritance pattern in the family (if parents are available).

Mendelian analysis in Sequence Miner

Example use case

The user has a nuclear family that includes both unaffected parents and two siblings affected with a disorder. The user suspects a recessive genetic variant is the cause and wishes to screen family members for variants that are heterozygous in the parents and homozygous or compound-heterozygous in the affected siblings.

Description of the algorithm

For all selected family members, the query first extracts all variant calls that meet the filtering criteria (e.g., variants of user-defined known or predicted pathogenicity level, allele frequency or impact on the transcript, variants residing in user-selected genomic regions of inclusion or omission, etc.). Each variant is comprehensively annotated with allele frequency, reported or predicted level of pathogenicity, clinical information, and other attributes. The annotated variants are then presented in several different perspectives: AllByGene, AllVariants, and inheritance patterns in the subjects. The index case will be considered “affected” or a “case”. If the parents are unaffected, they will be treated as “controls”. Additional siblings added to the analysis will be considered “cases” if they are affected or “controls” if they are unaffected.

The inheritance model is designated as follows:

DIAG_HomRecess if the following criteria are met:

• The index is homozygous for a variant meeting the user’s criteria OR if the variant is on the X chromosome, a male index is a hemizygous

• Neither parent is homozygous OR if the variant is on the X chromosome and if the father is a carrier, then he is affected

DIAG_CHZ if the following criteria are met:

• The index is a carrier of 2 different variants that meet the user’s criteria and reside in the same gene

• The variants are each contributed by a different parent

DIAG_Dominant if the following criteria are met:

• The index carries a variant with a max_Af < the user designated DmaxAf

• The parent who carries the variant is affected

DIAG_denovo if the following criteria are met:

• The index is a carrier of a variant meeting the user’s criteria and that has a VEP_max_Af < the user designated DmaxAf

• Both parents have coverage depth > 8 reads at the locus

• Both parents have fewer than 2 reads carrying the variant

Interpreting the output

The resulting output lists a single row per variant identified in the designated index case subject. The variants shown are filtered based on the criteria set by the user in the input parameters (e.g., call quality, read depth, allele frequency, VEP category, etc.). The variants are ordered by chromosome and position and annotated with coverage, quality metrics, variant counts by gene and affected status, as well as information from public clinical databases.

Based on the expected pattern of inheritance, the user may begin by reviewing the results in the corresponding inheritance perspective (e.g., ARhomAndCHZ - autosomal recessive and compound heterozygous variants). Alternatively, the review may start in the AllVariants perspective where the user can filter various columns by right-clicking the column header to select the filtering threshold for the selected column/attribute (e.g., columns for CASESwithHomoVar, FATHERwithVar, MOTHERwithVar).

Column descriptions

Basic columns and descriptions

Group	Column	Description
Basic
	Call
	CHROM
	hetORhom
	PN
	POS
	Reference

CGD columns and descriptions

Group	Column	Description
CGD		The CGD columns provide information for variants based on the manually curated database of variants associated with known medically significant conditions and available interventions
	AGE_GROUP	Pediatric: less than 18 years of age; Adult: At least 18 years of age
	COMMENTS	Any additional observations noted by curators
	CONDITION	Conditions resulting from mutations in the same gene but may otherwise be placed in the “General” Intervention category
	INHERITANCE	Pattern of inheritance: AD - autosomal dominant; AR - autosomal recessive; BG - blood group; Digenic - A condition resulting from simultaneous mutations in two different genes; Maternal - maternal mitochondrial inheritance; XL - X-linked (because X-linked conditions can frequently have manifestations in both genetic sexes, X-linked conditions are not designated as dominant or recessive)
	INTERVENTION_CATEGORIES	Includes organ systems for which specific and additional inteventions may be beneficial
	INTERVENTION RATIONALE	Description of the intervention and its benefit
	MANIFESTATION CATEGORIES	Includes organ systems affected by mutations in corresponding genes; recognition of involved organ systems may help guide supportive care
	REFERENCES	The pubmed ID (PMID) of the referenece(s)

COMM columns and descriptions

Group	Column	Description
COMM		COMM annotation is comprised of comments added by users in the project and comments drawn from the varcomments file (Knowledge Base)
	amcg_variant_annotation_id
	approval_months	Counter for number of months since the date of last approved clinical significance
	approved_clinical_significance	The clinical significance approved by the user
	bam_confirmed	The user’s notation if the BAM files were reviewed to confirm the presence/absence of the variant
	clinical_significance	The clinical significance (e.g., pathogenic, benign, unknown significance, drug-response, risk factor, etc.) of the variant as annotated (commented) by users; if the same variant has several comments, this cell will contain a set of values
	computation_data_indicator
	created_at	Date and time stamp the comment was created
	disease	The associated disease or phenotype
	extDiseaseDescription
	extDiseaseId
	extDiseaseName
	gene_prevalence_button
	gene_symbol	Gene symbol from the varcomments table
	hgvscp	The HGVS coding/protein sequence name
	id	Comment ID
	internal_comment	User comment created for internal use
	interpretation	Interpretation on a variant, added by the user
	is_active	User comment on Active status of the variant
	last_approved_at	The last time the variant was approved by the user
	mode_of_inheritance	The user-annotated (commented) mode of inheritance of the variant; if the same variant has several comments, this cell will contain a set of values
	onset	The onset of the disease the variant is associated with, curated by the user
	other_allele	User comment on the other allele
	other_databases_indicator
	owner	User name
	parental_origin	Parental origin of the variant selected by the user, e.g., father, mother, both, de novo, unknown, etc.
	pn	User comment on the patient
	population_data_indicator
	query_context
	report_section	Section in which the variant should be placed, selected by the user
	report_status	Indicates what to report, related to client workflow
	report_type	Type of report, related to client workflow
	reported_at	Date of variant annotation
	reporting_category	Reporting category selected by the user, related to client workflow
	sanger_status	User comment on the status of the confirmation by Sanger sequencing
	STARRED	A Boolean column indicating if the variant has been marked (starred) by users
	severity	Severity of the disease with which the variant is associated, added by the user
	text	The description (comment) component for the user annotation of the variant
	transcript
	transcript_raw	All possible transcripts with HGVS nomenclature for the variant that can be selected by the user
	transcriptFeature
	type
	user_id	User ID
	variant_annotation_related
	variant_review_status	Variant review status added by the user

DIAG columns and descriptions

Group	Columns	Description
DIAG		The DIAG columns provide diagnostic information for categorizing variants in a clinical setting based on the American College of Medical Genetics and Genomics (ACMG) guidelines. For reference, “diagnosis” is abbreviated as “dx” in some cases.
	ACMGcat	Categorization of the sequence variants according to the ACMG scheme
	CHZ	This field is equal to 1 (true) if the index is/cases are compound heterozygous (chz) (see GENE_CHZinGene) and none of the controls are homozygous
	deNovo	A Boolean column indicating if a variant is de novo, i.e., not present in the parents
	Dominant	The dominant variant; field is “true” if the variant is not present in unaffected individuals but is present in affected individuals
	HomRecess	The homozygous recessive variant; field is “true” if the variant is heterozygous in unaffected individuals but is present in affected individuals
	model	Autosomal or X-linked analysis
	otherACMGcat	The ACMG category of other variants (see DIAG_otherPos and DIAG_compPhases) that form compound heterozygosity with the variant
	otherPos	For a particular CHZ variant, the base pair position of the other variant(s) that produces compound heterozygosity in a gene
	rank_dominant	An emperical ranking of variants. Low-ranking variants are likely to be better candidates for dominant variants than those with a high rank. This ranking takes into consideration how many affected individuals share the same variant or any variants in the same gene, and how few controls have the variant or any variant in the same gene (see also DIAG_Dominant).
	rank_recessive	An emperical ranking of variants. Low-ranking variants are likely to be better candidates for recessive variants than those with a high rank. The ranking takes into consideration homozygosity and compound heterozygosity in the affected vs. unaffected individuals. Furthermore, the smaller the DIAG_recessiveCat value (e.g., “1:DxConsistent”, “2:DxLikely”, “3:DxPossible”, etc.), the larger the weight of the variant.
	recessiveCat	The recessive and compound heterozygosity category is based on the ACMG category for two alleles from any two variants observed in a gene or from a homozygous variant. For an allele combination in the index case to be considered a potential recessive or compound heterozygous candidate, it may not be present in any of the controls (unless ctrlDelta is greater than zero). If the alleles in the index can be phased, they are only considered if they are not known to be from the same parent. In controls, the phase of alleles is assumed to be different. Aggregate DIAG_recessiveCAT scores are calculated for homozygous and all possible compound heterozygous variant combinations per gene with the following 7 tests: 2 CAT1 variants or a CAT1 variant in combination with a CAT2 variant,’1:DxConsistent’ Either a CAT1 or CAT2 variant in combination with a CAT3A variant,’2:DxLikely’ Either 2 CAT3A variants or a CAT1, CAT2 or CAT3A variant in combination with a CAT3B variant, ‘3:DxPossible’ 2 CAT3B variants,’4:DxLessLikely’ A CAT1 or CAT2 variant in combination with a CAT4 variants, ‘5:DxIndeterminate’ A CAT3A or a CAT3B variant in combination with a CAT4 variant, ‘6:DxUnlikely’ Variant combinations that don’t meet any of the above criteria,’7:DxNegative’

EuroGenetest columns and descriptions

Group	Columns	Descriptions
EuroGenetest		The EuroGenetest columns are derived from a European Commission project database containing European genetic testing information for particular genes, variants, and diseases.
	Diseases	Diseases associated with a variant derived from the European Commission project database
	NoOfDiseases	Number of diseases associated with a variant derived from the European Commission project database
	NoOfpanels	Number of gene panels associated with a variant derived from the European Commission project database
	panels	EuroGenetest panels associated with a variant derived from the European Commission project database

FATHER columns and descriptions

Group	Columns	Description
FATHER		The FATHER columns provide variant annotations for the father. The same attributes are listed for the mother in the MOTHER group of columns.
	apprCovDepth	The approximate read depth of the given variant
	call	Sequence (variant) called based on the reference sequence at the designated position
	hetORhom	Heterozygous or homozygous of given variant
	homozVarsInGene	Equal to 1 if the father has some homozygous variant in the given gene
	knownVarsInGene	The number of known variants (e.g., in HGMD, ClinVar, OMIM) that the father has in the given gene
	readsWithVar	The number of reads contains the variant allele
	subjCompHeterInGene	Equal to 1 if the father has potentially compound heterozygous for a given gene, otherwise it is equal to 0. Compound heterozygosity requires the case to have a single homozygous variant or two heterozygous variants in a given gene.
	subjWithVarInGene	Equal to 1 if the father has variant in the given gene, otherwise it is equal to 0
	withHomoVar	Equal to 1 if the father is homozygous for a given variant
	withVar	Equal to 1 if the father has the variant, otherwise it is equal to 0

GENE columns and descriptions

Group	Columns	Description
GENE		The GENE columns provide information based on the candidate gene in which a variant is found. When possible, the HUGO Gene Nomenclature Committee (HGNC) gene symbol is provided.
	Aliases	Aliases of a given gene as annotated by Ensembl
	avg_depth	The average sequence read depth in the exome of a given gene
	candidate_paralogs	If the gene is a paralog of a designated candidate gene, then it is listed in this column
	CandorParalog	“c” indicates the gene is a designated candidate gene and “p” indicates the gene is a paralog of a designated candidate gene
	cov	The fraction of genes (exome) with depths <5 (L), ranging from 5-9 (M), and greater than 9 (H); the scale is from 0 to 1
	DmaxAf	The maximum allowed allele frequency for a dominant variant
	exomeSize	The sum of exon in the given gene
	exontype	The type of exon (“coding” or “noncoding”)
	homozVarsInGene	The number of homozygous variants the index case has in a given gene
	iheVarsInGene	The number of inheritance error variants the index case has in a given gene
	knownVarsInGene	The number of known (e.g., in HGMD) variants the the index case has in a given gene
	lt10	The fraction of the exome with sequence read coverage less than 10X
	lt15	The fraction of the exome with sequence read coverage less than 15X
	lt20	The fraction of the exome with sequence read coverage less than 20X
	lt25	The fraction of the exome with sequence read coverage less than 25X
	lt30	The fraction of the exome with sequence read coverage less than 30X
	lt5	The fraction of the exome with sequence read coverage less than 5X
	maximum_allele_freq_for_dominant
	maximum_allele_freq_for_recessive
	maximum_genotype_freq_for_recessive
	MOI	Mode of inheritance
	Paralogs	The paralogs of a given gene
	symbol	Gene identified by viewing variant in Ensembl; outputs HGNC gene symbol for gene identified (clone name provided when HGNC unavailable)
	varsInGene	The total number of variants in a gene for the index case

GO columns and descriptions

Group	Column	Description
GO		The GO columns provide a functional annotation of the gene product in which the variant is found
	Descriptions	Gene ontology descriptions
	IDs	Gene ontology identifiers

GT columns and descriptions

Group	Column	Description
GT		The GT (genotype attributes) gruop of columns provide quality control information for the variant call based on the sequence read depth and quality
	CallCopies	Refers to how many copies of the variation exist in a subject. A CallCopies value of “2” therefore corresponds to a homozygous variant; a CallCopies value of “1” corresponds to a heterozygous variation; a CallCopies of “0” corresponds to No Call
	CallRatio	Proportion of reads containing the variant call; expected to be approximately 0.5 for heterozygous calls and close to 1 for homozygous calls
	Depth	The number of reads used for evaluating the corresponding call
	FILTER	Quality parameter using the ratio between gt-quality and depth, showing if the call is considered “LowQual” quality or “PASS”
	GL_Call	A statistical measure indicating the likelihood that the call is wrong; the scale has been converted to use only integers - the higher the number, the less likely it is that the call is wrong
	IHEstatus	A Boolean column (1/0) indicating whether the variant is an inheritence error or not; “1” indicates that the variant is an inheritance error, “0” indicates that the variant is not an inheritance error

KNOWN columns and descriptions

Group	Column	Description
KNOWN		The KNOWN columns provide publicly available information about the candidate gene and/or variant as annotated by HGMD, ClinVar, and OMIM.
	ClinVarAcc	The associated ClinVar accession ID
	distance	The distance between a known pathogenic variant (Cat1, pathogenic annotation in HGMD, ClinVar, or OMIM) and the identified variant
	exactMatch	A Boolean column (1/0) indicating if the variant (chromosome, position, reference, call) is a direct match to a known pathogenic variant (instead of near a known variant, or at the same position with a different call allele)
	Gene_diseases	Diseases known to be associated with the gene as annotated by HGMD, ClinVar, and OMIM
	Gene_par_diseases	Diseases known to be associated with the parlogs of the gene as annotated by HGMD, ClinVar, and OMIM
	GeneLists	Pre-defined gene list membership of the gene in which the variant is found
	HGMDacc	The related HGMD accession ID
	InACMG	A Boolean column (1/0) indicating whether the gene is in the ACMG recommended list for incidental findings
	pmid	Pubmed ID of the reference from which the information was obtained
	source	The public database (ClinVar, HGMD, or OMIM) source for annotation
	var_diseases	Diseases known to be associated with the variant as annotated by HGMD, ClinVar, and OMIM
	variantType	The type of the variant (germline, pathogenic, etc.)

MOTHER columns and descriptions

Group	Columns	Descriptions
MOTHER		The MOTHER columns provide variant annotations for the mother. The same attributes are listed for the father in the FATHER group of columns.
	apprCovDepth	The approximate read depth of the given variant
	call	Sequence (variant) called based on the reference sequence at the designated position
	hetORhom	Heterozygous or homozygous of given variant
	homozVarsInGene	Equal to 1 if the mother has some homozygous variant in the given gene
	knownVarsInGene	The number of known variants (e.g., in HGMD, ClinVar, OMIM) that the mother has in the given gene
	readsWithVar	The number of reads contains the variant allele
	subjCompHeterInGene	Equal to 1 if the mother has potentially compound heterozygous for a given gene, otherwise it is equal to 0. Compound heterozygosity requires the case to have a single homozygous variant or two heterozygous variants in a given gene.
	subjWithVarInGene	Equal to 1 if the mother has variant in the given gene, otherwise it is equal to 0
	withHomoVar	Equal to 1 if the mother is homozygous for a given variant
	withVar	Equal to 1 if the mother has the variant, otherwise it is equal to 0

OMIM columns and descriptions

Group	Column	Description
OMIM		The OMIM columns provide the OMIM-designated identification for a particular gene and related disease description.
	Descriptions	OMIM disease descriptions for the gene
	IDs	The OMIM ID of the gene

VEP columns and descriptions

Group	Column	Description
VEP		The VEP (Variant Effect Predictor) columns provide functional annotations for variants based on the ENSEMBL SNP Effect Predictor database. For more information, visit the VEP web page: http://www.ensembl.org/info/docs/tools/vep/index.html/.
	Amino_acids	The amino acid with and without variant (only provided if the variation affects the protein-coding sequence), otherwise “.”
	Biotype	Biological class of transcript or regulatory feature
	CDS_position	Position of the base pair in the coding sequence; a value is given for each transcript
	Consequence	The Variant Effect Predictor annotation of the consequence type in the canonical transcript of the annotated variant
	Max_Af	Maximum reported allele frequency across the population surveys from 1000GP3, EVS, EXAC, Kyoto, GONL (Variant View - Frequencies)
	Max_Consequence	VEP predicted consequence for a variant producing the the greatest impact on the transcript
	Max_Impact	Classification of the level of severity of the transcript consequence type assigned by VEP
	Max_Score	Maximum score for the variant as observed in dbNSFP [Score=max ((1-Sift_score), Polyphen2_HDIV_score, Polyphen2_HVAR_score)].
	Protein_position	Position of the amino acid in the protein sequence (only if the variant falls within a coding sequence); a value is given for each corresponding transcript specified in the CDS position field
	Refgene	The accession number from NCBI of the affected transcripts
	Transcript_count	The number of different transcripts in which the variant is found

Other columns and descriptions

Group	Column	Description
Other columns
	Biotype	Additional annotation using Ensembl lookup based on feature, e.g., miRNA_PUTATIVE, misc_RNA_PUTATIVE, protein_coding_PUTATIVE, pseudogene_PUTATIVE, snoRNA_PUTATIVE
	Carrier	Indicates if the individual carries the variant (“true” or “false”)
	CLNACC	ClinVar assigned variant accession number
	formatZip	VCF genotype fields
	FS	Fisher’s exact test of read strand; if the reference reads are balanced between forward and reverse strands, then the alternate reads should be as well
	HGVSc	The HGVS coding sequence name
	HGVSp	The HGVS protein sequence name
	ID	Identifier, either hgmd or pmid/omim in clinical detail map
	Refgene	mRNA accession number from NCBI using lookup into Ensembl using feature
	rsIDs	rsID of the SNP entry in dbSNP, corresponding to the mutation, where available
	Sequence_Variant	The formatted sequence variant
	Source	This column lists the parent/source (one parent) of the corresponding row variant
	Sourcex	This column lists the other parent/source of the corresponding row variant
	varType	“del” for deletion, “ins” for insertion, and “sub” for substitution

Perspective views

The Default view perspective shows all of the columns described above. Additional perspectives focus on subsets of the columns in the default view.

Perspectives

Perspective	Description
ACMG
AllByGene	Focuses on all variants that meet the user’s criteria and all genes carrying such variants
AllKnownVariants
AllVariants	Focuses on all variants that meet the user’s criteria and all genes carrying such variants
ARhomAndCHZ	Focuses on all variants that meet the user’s criteria and that fit the corresponding inheritance models
AutoRecessHom	Focuses on all variants that meet the user’s criteria and that fit the corresponding inheritance models
CandidateGenesByGene	Focuses on variants that meet the user’s criteria and are in the user’s selected candidate genes (when applicable)
CandidateGenesByVar	Focuses on variants that meet the user’s criteria and are in the user’s selected candidate genes (when applicable)
CommentedVariants	All variants in the index that meet the user’s criteria and that have been previously annotated by a user
CompoundHetero	Focuses on all variants that meet the user’s criteria and that fit the corresponding inheritance models
Default view	Shows all columns
DeNovoInCandidates	Focuses on variants that meet the user’s criteria and are in the user’s selected candidate genes (when applicable)
Dominant	Focuses on all variants that meet the user’s criteria and that fit the corresponding inheritance models
gene_panelGenesByGene	Focuses on variants that meet the user’s criteria and are in genes from the user’s selected gene panel (or paralogs). When the user enters a gene_panel as an optional parameter, results will be displayed only for variants in those genes
gene_panelGenesByVar	Focuses on variants that meet the user’s criteria and are in genes from the user’s selected gene panel (or paralogs). When the user enters a gene_panel as an optional parameter, results will be displayed only for variants in those genes
KnownVariants	focuses on variants that meet the user’s criteria and are known pathogenic variants reported in HGMD, OMIM, or ClinVar
MissKnownDiseaseGenes	Focuses on known pathogenic variants missing from the index but that meet any of the following criteria: Homozygous in either parent Present in all cases Exhibit very low sequence coverage
MissKnownVarsInCandGenes	Focuses on candidate gene (or paralogs) variants missing from the index but that meet any of the following criteria: Homozygous in either parent Present in all cases Exhibit very low sequence coverage
OMIM
PossMissInCandGenes	Focuses on candidate gene (or paralogs) variants missing from the index but that meet any of the following criteria: Present in either parent Present in all cases Exhibit very low sequence coverage
XlinkedRecess	Focus on all variants that meet the user’s criteria and that fit the corresponding inheritance models

Drill-in reports

Drill-in reports

Drill-in	Description
CaseAndControl_Variants	For the selected gene variant in the Mendel report, this drill-in report lists the variant genotype for each carrier
CaseAndControl_VarsInGene	For the selected gene variant in the Mendel report, this drill-in report lists all case and controls variants in the same gene with any of the user-selected maximum consequences and the variant genotype for each carrier
CaseAndControl_AllVarsInGene	For the selected gene variant in the Mendel report, this drill-in report lists all variants identified in the same gene as the selected gene variant and the genotype for each carrier