VarSome: The Human Genomic Variant Search Engine

Abstract

SummaryVarSome.com is a search engine, aggregator and impact analysis tool for human genetic variation and a community-driven project aiming at sharing global expertise on human variants.AvailabilityVarSome is freely available at http://varsome.com.

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort

“…The CNNM4 c.706C > T (p.Arg236Trp) variant creates a nonconservative substitution in the protein in a highly conserved residue (GERP score 4.99) located in the DUF21 domain of the protein. The missense variant p.Arg236Trp was predicted to be damaging by 14 different in‐silico prediction tools (SIFT, PolyPhen2, PROVEAN, DANN, DEOGEN2, EIGEN, FATHMM‐MKL, M‐CAP, MVP, MutationAssess, MutationTaster, REVEL, MetaSVM, MetaLR) whereas it was predicted benign by only one in‐silico tool (PrimateAI) (Kopanos et al, ). Also, the missense variant p.Arg236Trp had a high CADD score (Rentzsch, Witten, Cooper, Shendure, & Kircher, ) of 32, while the gnomAD missense Z score (2.37) indicates that CNNM4 gene is moderately constrained against missense changes.…”

The Clinical Genome and Ancestry Report: An interactive web application for prioritizing clinically implicated variants from genome sequencing data with ancestry composition

“…Further details on each variant can be found by clicking the plus button on the left of each gene symbol. Expanded child row (Figure b, bottom) contains the links to a pop‐up window for detailed information on the variant and links to external server including gnomAD, MARRVEL (Wang et al, ), VarSome (Kopanos et al, ), Beacon Network (Global Alliance for Genomics & Health, ), WEScover, a web application showing gnomAD WES coverage data organized by genes and populations (Alvarez et al, ), and VarSite (Stephenson, Laskowski, Nightingale, Hurles, & Thornton, ). The link to detailed view opens a new window with further details for each variant including: (1) calculated variant consequence for each transcript with predicted pathogenicity scores from multiple algorithms; (2) allele frequencies from the 1000 Genomes Project, gnomAD, and the Exome Sequencing Project summarized by ancestral populations; (3) scores for predicted effect on splice sites; (4) locus‐specific conservation scores; (5) protein families or domains overlapping with the locus; and (6) a list of PubMed entries on the variants extracted from VEP annotation.…”

“…We compared the features available in CGAR with three recently published tools for variant interpretation—MARRVEL (Wang et al, ), VarSome (Kopanos et al, ), and VarCards (J. Li et al, ) (Table ). MARRVEL was developed for interpreting filtered candidate variants from patients with rare diseases and can take gene symbol, DNA or protein variant as input.…”

“…To this end, diverse locus‐, gene‐, and phenotype‐centric databases provide information on phenotype‐associated variants and genes (Amberger, Bocchini, Scott, & Hamosh, ; Landrum et al, ; Stenson et al, ). The Model organism Aggregated Resources for Rare Variant ExpLoration (MARRVEL) and VarSome provide comprehensive information for each variant by integrating multiple resources (Kopanos et al, ; Wang et al, ). The work required to use these databases is substantial, including narrowing down the list of variants by searching multiple databases, verifying detailed information in variant‐centric databases, and incorporating other criteria such as minor allele frequency in an ancestry‐matched population.…”

Identification and functional characterization of a novel heterozygous missense variant in the LPL associated with recurrent hypertriglyceridemia‐induced acute pancreatitis in pregnancy

“…The Combined Annotation‐Dependent Depletion (CADD) tool (Kircher et al, ) and the PP3 rule established by VarSome (Kopanos et al, ) were employed to predict the pathogenicity of the LPL missense variant detected. CADD integrates more than 60 diverse annotations into a single measure (C‐score) for each variant, with a C‐score of >20 being regarded as evidence of pathogenicity.…”