Internal annotations

The Internal annotations report builder compiles and annotates a list of variants or genes with variants in the project that have been commented on in Clinical Sequence Analyzer (CSA) or Sequence Miner (SM). Annotation is based on the selected reportMode (byGene or byVariant) and whether the user selects “yes” or “no” to includePhenotypes.

Internal Annotations module in Sequence Miner

Example use case

The user wishes to compile a list of all variants in the project that are related to cardiomyopathy and that have been annotated (commented on) by all users in the project. The user runs the Comments report builder setting reportMode to “byVariant” and selects “yes” to includePhenotypes. The user then filters the description column on cardiomyopathy.

Description of the algorithm

Variants or genes with variants that have been commented on internally (by users in the project) are retrieved and joined with corresponding annotation tables based on the selected report format.

Interpreting the output

Column headers for annotations are described in the tables below. Annotation from numerous sources are provided. These include VEP, allele frequency and ACMG Category for variants and GO, OMIM, ClinVar and HGMD for genes.

Column descriptions

Columns in both reports (byGene and byVariant)

Column	Description
Chrom	The chromosome of the variant represented as chr1, chr2, …, chr22, chrXY, chrX, chrY, chrM
gene_symbol	Based on HGNC when it exists, otherwise it is the Ensembl internal alias
set_clinical_significance	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 multiple associated comments, this cell will contain a set of values
set_mode_of_inheritance	User annotated (commented) mode of inheritance of the variant; if the same variant has multiple associated comments, this cell will contain a set of values
code	HPO or OMIM taxonomy code for designated phenotype (shown only when includePhenotypes is set to “yes”)
description	HPO or OMIM description for designated phenotype (shown only when includePhenotypes is set to “yes”)

Columns specific to byGene reports

Column	Description
gene_start	The start base-pair position of the gene (zero based, i.e., the position of the base-pair before the first base-pair in the gene)
gene_end	Coordinate of the last nucleotide on the gene
GENE_Aliases	The aliases of the given gene
GENE_Paralogs	The paralogs of the given gene
GO_IDs	Gene Ontology identifiers
GO_Descriptions	Gene Ontology category descriptions
KNOWN_Gene_diseases	Diseases known to be associated with the gene as annotated by HGMD, ClinVar, and OMIM
KNOWN_lis_disease	Diseases known to be associated with the gene as annotated by HGMD, ClinVar, and OMIM
KNOWN_MaxClinImpact	The maximum clinical consequence of the variant (pathogenic, unknown etc) annotated by any one of HGMD, OMIM or ClinVar
OMIM_IDs	OMIM ID of the gene
OMIM_Descriptions	OMIM disease descriptions for the gene
dis_PN	Number of carriers of this variant with comments

Columns specific to byVariant reports

Column	Description
pos	The (first) basepair position of the sequence variant, e.g., the position of the first nucleotide in the Reference column
ref	Reference allele in vcf format
alt	Alternative allele in vcf format
VEP_Amino_Acids	The amino acid with and without variant (only provided if the variant affects the protein-coding sequence), otherwise “.”
VEP_Biotype	Biological class of transcript or regulatory feature
VEP_CDS_position	Position of the base pair in the coding sequence; a value is given for each transcript
VEP_max_consequence	VEP predicted consequence for a variant producing the the greatest impact on the transcript
VEP_Max_Impact	Classification of the level of severity of the transcript consequence type assigned by VEP
VEP_Max_Score	Maximum score for the variant as observed in dbNSFP [Score=max ((1-Sift_score), Polyphen2_HDIV_score, Polyphen2_HVAR_score)]
VEP_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
VEP_Refgene	The Accession number from NCBI of the affected transcripts
VEP_Transcript_count	Number of different transcripts in which the variant is found
MAX_AF	Maximum reported allele frequency (1000GP3, EVS, EXAC, Kyoto, GONL)
set_pn	IDs of a variant carriers
DIAG_ACMGcat	Categorization of the likelihood pathogenicity of sequence variants according to the ACMG scheme; values range from cat1 (most severe) to cat4 (least severe). See table below for ACMG categorization descriptions.