MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains

Abstract

The growing availability of human genetic variation has given rise to novel methods of measuring genetic tolerance that better interpret variants of unknown significance. We recently developed a concept based on protein domain homology in the human genome to improve variant interpretation. For this purpose, we mapped population variation from the Exome Aggregation Consortium (ExAC) and pathogenic mutations from the Human Gene Mutation Database (HGMD) onto Pfam protein domains. The aggregation of these variation data across homologous domains into meta‐domains allowed us to generate amino acid resolution of genetic intolerance profiles for human protein domains. Here, we developed MetaDome, a fast and easy‐to‐use web server that visualizes meta‐domain information and gene‐wide profiles of genetic tolerance. We updated the underlying data of MetaDome to contain information from 56,319 human transcripts, 71,419 protein domains, 12,164,292 genetic variants from gnomAD, and 34,076 pathogenic mutations from ClinVar. MetaDome allows researchers to easily investigate their variants of interest for the presence or absence of variation at corresponding positions within homologous domains. We illustrate the added value of MetaDome by an example that highlights how it may help in the interpretation of variants of unknown significance. The MetaDome web server is freely accessible at https://stuart.radboudumc.nl/metadome.

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

“…Human Genome Variation Society nomenclature (http://varnomen.hgvs.org) was used for variant notation, with the A of the initiation codon ATG as +1. The functional impact of identified sequence variants was assessed trough in silico predictions in Alamut Visual (v.2.8.1), Alamut Batch (v.1.9), and dbNSFP (v.3.4a), including missense prediction tools, splice prediction tools, physicochemical distance (Grantham score), evolutionary conservation, location in protein domains, presence in dbSNP (build 151—https://www.ncbi.nlm.nih.gov/SNP), MetaDome (https://stuart.radboudumc.nl/metadome/—v.1.0.1), Exome Variant Server from the NHLBI Exome Sequencing Project (ESP—http://evs.gs.washington.edu/EVS), ExAC (http://exac.broadinstitute.org/), and gnomAD (http://gnomad.broadinstitute.org/; Liu, Wu, Li, & Boerwinkle, 2016; Wiel et al, 2019).…”

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

“…Among the six genes, CACNB4 has the lowest o/e score for missense variants (0.55) indicating that this gene is under selection and probably a Mendelian disease gene (S1 Table). In addition, we used the MetaDome web server, which provides profiles of genetic tolerance through aggregation of homologous human protein domains [70]. MetaDome predicted leucine 126 of CACNB4 to be highly intolerant, while the genetic tolerance of the amino acid residues affected in the other five genes ranges from neutral to intolerant (S1 Table).…”

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

“…No other amino acid changes affecting Cys179 or other highly conserved cysteines of the DSL domain of DLL1 and other Notch ligands are present in gnomAD or ClinVar, suggesting reduced tolerance to variation in this important domain ( Figure 3B). 20,[25][26][27] No LoF variants in DLL1 are reported in control cohorts, indicating intolerance to LoF (gnomAD pLI score ¼ 1.0). In individual 15 (F12/II-1 in Figure 1A) with the microdeletion of DLL1, the only other gene located within the deletion was FAM120B (MIM: 612266), a gene not known to be associated with neurodevelopmental issues and is expected to be tolerant to LoF (gnomAD pLI score ¼ 0), suggesting that the deletion of DLL1 causes the phenotype in this individual.…”

“…Top: visualization of the MetaDome score. 26 Center: multi sequence alignment (MSA) of the DSL domain of genes annotated with DSL domain by Prosite (DLL1, DLL4, JAG1, JAG4). Positions with missense variants in gnomAD version 2.1 as well as pathogenic ClinVar variants are labeled (no frameshift and nonsense variants are present in gnomAD).…”