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

Abstract

199/200) 20The growing availability of human genetic variation has given rise to novel methods of 21 measuring genetic tolerance that better interpret variants of unknown significance. We recently 22 developed a novel concept based on protein domain homology in the human genome to improve 23 variant interpretation. For this purpose we mapped population variation from the Exome 24 Aggregation Consortium (ExAC) and pathogenic mutations from the Human Gene Mutation 25 Database (HGMD) onto Pfam protein domains. The aggregation of these variation data across 26 homologous domains into meta-domains allowed us to generate base-pair resolution of genetic 27 intolerance profiles for human protein domains. 28Here we developed MetaDome, a fast and easy-to-use web service that visualizes meta-domain 29 information and gene-wide profiles of genetic tolerance. We updated the underlying data of 30 MetaDome to contain information from 56,319 human transcripts, 71,419 protein domains, 31 12,164,292 genetic variants from gnomAD, and 34,076 pathogenic mutations from ClinVar. 32MetaDome allows researchers to easily investigate their variants of interest for the presence or 33 absence of variation at corresponding positions within homologous domains. We illustrate the 34 added value of MetaDome by an example that highlights how it may help in the interpretation of 35 variants of unknown significance. The MetaDome web server is freely accessible at 36 https://stuart.radboudumc.nl/metadome. 37

De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

“…This ratio is computed into a tolerance landscape as a sliding window of 11 residues over the protein. 30 For KDM3B, this plot shows intolerance for missense variation in and nearby the zinc-finger and Jumonji-C domains, where most of the missense mutations identified in the individuals described in this paper are located. (C) Protein alignment of KDM3B orthologs across several species.…”

“…To further determine the effect of the missense variants identified, we used the MetaDome web server to generate a tolerance landscape of KDM3B ( Figure 1B). 30 This server uses the gnomAD database to calculate a missense-over-synonymous ratio as a sliding window over the protein. This ratio is then expressed as a tolerance landscape.…”

Variants in the NPC1 Gene in Egyptian Patients with Niemann-Pick Type C

“…Although they are widely scattered over the geneother studies considered some regions such as residues(855-1098) in the cysteine-rich luminal loop and residues(1038-1253) which shares 34.7% with PTC1, as hot spot regions for NPC disease mutations [34]. In this study, molecular analysis of nine exons (17)(18)(19)(20)(21)(22)(23)(24)(25) of NPC1 encountering the previously suggested hot spot residues(855-1098) and (1038-1253) revealed six different mutations (15 mutant alleles) in eightunrelated patients. Regarding the high consanguinity rate in our population, homozygous mutations were predominated.…”

“…Functional prediction analysis, including PolyPhen2 [22], SIFT [23], and Mutation Taster [24], was used to evaluate the functional effect of novel nonsynonymous amino acid substitutions. NPC1mutation tolerance was further analyzed usingthe MetaDome webserver [25].…”

Mutational Survivorship Bias: The case of PNKP

“…Low confidence variants were not considered. To obtain further information on genetic tolerance of mutations in PNKP, we used the MetaDome server (Wiel et al, 2019) to plot the mutational tolerance landscape of each domain. Mann-Whitney U test will be used to compare the average dN/dS ratio between domains.…”