Carrier¶

The Carrier report builder analyzes variants in parents to identify potential disease-causing variants that are heterozygous in the parents and could be inherited by a child to produce a recessive disorder.

Example use case¶

The user wishes to screen whole exome sequencing (WES) reads from expectant parents to identify all sequence variants that may be inherited by their offspring. The user designates several filters to apply to the identified variants: a range of VEP consequences, maximum allele frequency, a target range of whole genome or exon-only, and sequence quality thresholds.

Description of the algorithm¶

The algorithm extracts all variants from the VEP whole exome file (source/anno/vep_v3-4-2/vep_single_wes.gord) that meet the user’s filtering criteria for max_consequence (maximum predicted consequence) and max_af (maximum allele frequency). Annotation from the clinical_variants.gorz file is joined to Known pathogenic variants in this subset in order to include the clinical database source (HGMD, ClinVar or OMIM in the Known_dbSource column), Gene_diseases, MaxClinImpact, and Var_diseases. Further annotation includes coverage-per-base and average coverage across a 10 base window (within +/- 5 bases adjacent to the variant).

Interpreting the output¶

The results are summarized in four different perspectives:

Default view - Results are presented in multiple columns of annotation including zygosity; VEP-predicted consequence, impact and score; genomic coordinates; descriptions; gene ontology ID; OMIM ID; etc.

InBothParents - This perspective presents only the subset of identified variants that meet the applied filters and that are present in both parents.

RecessiveCandidates - This perspective presents all variants that meet the applied filters and for which either or both parents are heterozygous.

RecessiveKnownVar - Recessive known variants are those present in either parent and that are reported in HGMD, ClinVar or OMIM as known Category 1 (pathogenic) variants.

Column descriptions¶

Report output columns and descriptions¶
Group	Column	Description
Basic	CHROM
	POS
	Reference
father	CallRatio	Proportion of reads containing the variation call; expected to be close to 0.5 for heterozygous calls and close to 1 for homozygous calls
	Depth	The number of reads used in evaluating the corresponding call
	extCovAvgDepth10	The coverage depth extracted for variants and averaged across a 10 base window centered on the variant, meaning within 5bp on either side of the variant
	extCovDepth	The depth of coverage at the variant nucleotide(s)
	FILTER	Quality parameter using the ratio between gt-quality and depth showing if the call is considered of LowQual quality or acceptable quality (PASS); this is a crude quality measure
	formatZip	VCF genotype field
	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
	genesum_het	The sum of the number of heterozygous variants for a given gene
	genesum_hom	The sum of the number of homozygous variants for a given gene
	genesum_miss	The number of variants in the gene that have coverage less than 8 and are therefore excluded from the analysis
	GL_call	A statistical measure indicating the likelihood that the call is wrong; the scale has been converted to use only integer numbers - the higher the number, the less likely that the call is wrong
	het	Boolean for hereozygosity (1) or absence of heterozygosity (0) of the variant defined by a CallCopies value = 1
	hetORhom	“hom” for homozygosity and “het” for heterozygosity
	hom	Boolean for homozygosity (1) or absence of homozygosity (0) of the variant defined by a CallCopies value = 2
	miss	A Boolean column set to 1 if the variant has coverage less than 8
	PN	Subject ID
	vcf_alt	Alternate (variant) nucleotide sequence as reported in the vcf
	vcf_pos	Coordinate (position) of the reference nucleotide sequence
	vcf_ref	Reference nucleotide sequence
Gene	Aliases	Aliases of the given gene
	biotype	Biological class of gene
	cdsEnd	cDNA end position
	cdsStart	cDNA start position
	Description	Description of the gene, i.e. full gene name
	gene_stable_id	Ensembl stable ID for the gene
	Paralogs	Paralogs of the given gene
	Pathways	Biological pathway in which a given gene is found
	Strand	Strand of the gene
	Symbol	Based on HGNC when it exists, otherwise it is the Ensembl internal alias
GO	Description	Gene ontology category description
	IDs	Gene ontology identifiers
KNOWN	dbsource	Variants known in one of the following databases: HGMD, OMIM and ClinVar
	Gene_diseases	Diseases known to be associated with the gene as annotated by the dbsource column
	MaxClinImpact	The maximum clinical consequence of the variant (pathogenic, unknown etc) annotated by any one of HGMD, OMIM or ClinVar
	var_diseases	Diseases known to be associated with the variant as annotated by the dbsource column
lis	dbSourceMaxClinImpact
	disease
mother	Same columns as in father group	Same as described in father group
OMIM	Descriptions	OMIM disease descriptions for the gene
	IDs	OMIM ID of the gene
VEP	Amino_Acids	Amino acid with and without mutation (only provided if the variation affects the protein-coding sequence), otherwise “.”
	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 transcipt specified in the CDS position field
Other columns	Allele	Alternative allele in VCF format
	DIAG_AMCGcat	Categorization of the likelihood of pathogenicity of sequence variants according to the ACMG scheme; values range from cat1 (most severe) to cat4 (least severe); see AMCG categories below
	MAX_AF	Maximum reported allele frequency across the population surveys from 1000GP3, EVS, EXAC, Kyoto, GONL`
	MaxClinImpact	Max clinical impact from the clinImpact column
	Recessive	Indicates whether the child has a high probability of being recessive for a variant or not (“true” or “false”); “true” means the father and mother are heterozygous for a variant or compound heterozygous for the gene
	set_pathway	List of Ensembl pathways annotated for this gene from BIOCYC,HGMD,KEGG, Pathway Interaction Database (PID), REACTOME, and WikiPathways

AMCG categories¶

../_images/ACMG_categories.png — AMCG categories¶

Perspective views¶

The Default view perspective lists all variants. Additional perspectives focus on subsets of the columns in the default view.

Perspectives¶
Perspective	Description
Default view	Lists all variants
InBothParents	The variant is categorized as “recessive” (condition 1); the variant is heterozygous or homozygous in both father and mother (condition 2); the gene is related to known disease (condition 3); (Recessive = ‘true’ and FATHER_hetORhom != ‘’ and MOTHER_hetORhom != ‘’ and (len(KNOWN_Gene_diseases)>1 or len(OMIM_Descriptions)>1))
RecessiveCandidates	The variant is categorized as “recessive” (condition 1); the gene is related to a known disease (condition 2). This criterion is less stringent than InBothParents (Recessive = ‘true’ and (len(KNOWN_Gene_diseases)>1 or len(OMIM_Descriptions)>1))
RecessiveKnownVar	The variant is categorized as “recessive” (condition 1); the variant is a known pathogenic variant labeled ‘cat1’ (condition 2)

Drill-in reports¶

Drill-in reports¶
Drill-in	Description
GeneVariantsInParents	For the selected gene variant, this drill-in report lists all variants in the same gene that are carried by the parents