VarMap: a web tool for mapping genomic coordinates to protein sequence and structure and retrieving protein structural annotations

Abstract

Motivation Understanding the protein structural context and patterning on proteins of genomic variants can help to separate benign from pathogenic variants and reveal molecular consequences. However, mapping genomic coordinates to protein structures is non-trivial, complicated by alternative splicing and transcript evidence. Results Here we present VarMap, a web tool for mapping a list of chromosome coordinates to canonical UniProt sequences and associated protein 3D structures, including validation checks, and annotating them with structural information. Availability and implementation https://www.ebi.ac.uk/thornton-srv/databases/VarMap. Supplementary information Supplementary data are available at Bioinformatics online.

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.…”

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

“…The Rare Exome Variant Ensemble Learner (REVEL; Ioannidis et al, 2016) and Combined Annotation Dependent Depletion (CADD scores; Rentzsch, Witten, Cooper, Shendure, & Kircher, 2019) for all the variants in this study were obtained using Variant Ranker (http://vsranker.broadinstitute.org/; Du et al, 2019). The impact of each variant on the CALPAIN 3 protein structure was assessed using VarMap web tool (Stephenson, Laskowski, Nightingale, Hurles, & Thornton, 2019). SpliceAI scores for the variants were obtained using SpliceAI tool (v1.3, https://github.com/Illumina/SpliceAI; Jaganathan et al, 2019).…”

“…PM1 score was assigned for variants affecting highly conserved positions located in the Protease Core subdomains 1 and 2 (PC1 and PC2) of the Calpain‐type cysteine Protease conserved (CysPc) domain (amino acids 48–267, 316–415), in the calpain‐type β‐sandwich domain (CBSW, amino acids 429–586), or in the penta‐EF‐hand domain (PEF, amino acids 647–821; Ono, Ojima, Shinkai‐Ouchi, Hata, & Sorimachi, 2016; Ye, Campbell, & Davies, 2018). The position conservation was visualized by the VarMap web tool (Stephenson et al, 2019). PM3 score ( in trans with a pathogenic variant) was assigned according to the SVI Recommendation for in trans Criterion (PM3)—Version 1.0).…”

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

“…The REVEL (Ioannidis et al 2016) and CADD scores (Rentzsch et al 2019) for all the variants in this study were obtained using Variant Ranker (http://vsranker.broadinstitute.org/, (Alexander et al 2017)). Variant impact of calpain3 protein structure was assessed using VarMap web tool (Stephenson et al 2019). SpliceAI scores for the variants were obtained using SpliceAI tool (v1.3, https://github.com/Illumina/SpliceAI (Jaganathan et al 2019)).…”

“…PP3 was also assigned if two out of three algorithms (HSF, MaxEntScan, SpliceAI) indicated an impact on splicing. PM1 score was assigned for variants affecting highly conserved positions located in the Calpain catalytic domain (PF00648, amino acids 74-417), in Calpain III domain (PF01067, amino acids 436-579) or in EF-hand domains (amino acids 649-683; 692-718; 722-757; 787-821), as visualized by VarMap web tool (Stephenson et al 2019). PM3 score ( in trans with a pathogenic variant) was assigned according to SVI Recommendation for in trans Criterion (PM3) - Version 1.0).…”