MetaDome

MetaDome aggregates protein-domain homology and human variant data to generate amino-acid-resolution genetic intolerance profiles that support interpretation of human genetic variants.

Key Features:

• Variant and mutation mapping: Maps population variants from the Exome Aggregation Consortium (ExAC) and gnomAD, and pathogenic mutations from the Human Gene Mutation Database (HGMD) and ClinVar onto Pfam protein domains.
• Meta-domain aggregation: Aggregates mapped variants across homologous Pfam domains into meta-domains to increase statistical power for domain position analysis.
• Amino-acid-resolution intolerance profiles: Generates genetic intolerance profiles at amino-acid resolution for human protein domains to highlight tolerant and intolerant positions.
• Comprehensive database content: Includes data for 56,319 human transcripts, 71,419 protein domains, 12,164,292 genetic variants from gnomAD, and 34,076 pathogenic mutations from ClinVar.
• Homology-based position comparison: Enables position-wise comparison of presence or absence of variation across homologous domain positions to contextualize individual variants.

Scientific Applications:

• Interpretation of variants of unknown significance (VUS): Provides homologous-domain context to assess whether a specific variant occurs at positions tolerant or intolerant to variation.
• Pathogenicity analysis: Supplies aggregated domain-level evidence to inform pathogenicity assessments of missense and other coding variants.
• Genomic research on genetic tolerance: Supports studies of protein-domain tolerance landscapes and comparative analyses across human transcripts and domains.

Methodology:

MetaDome maps population variants (ExAC, gnomAD) and pathogenic mutations (HGMD, ClinVar) onto Pfam protein domains, aggregates these mappings across homologous domains into meta-domains, and derives amino-acid-resolution genetic intolerance profiles; the underlying database contains 56,319 transcripts, 71,419 domains, 12,164,292 gnomAD variants, and 34,076 ClinVar pathogenic mutations.