MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains.

Aggregation of population and pathogenic variants across homologous Pfam domain positions in the human proteome (meta-domains)

MetaDome aggregates population and pathogenic variation across homologous Pfam domain instances in the human proteome (meta-domains), providing per-residue context for interpreting variants of uncertain significance; the 2019 version is named in clinical variant-classification guidelines. The MetaDome 2027 update brings a comprehensively updated dataset, GRCh38 support and a pipeline enabling incremental updates of GENCODE, UniProtKB/Swiss-Prot, Pfam, gnomAD and ClinVar. Annotated Pfam domain instances grew from 71,419 to 82,069 and meta-domain-eligible families from 3,334 to 5,778; about 43% of mapped protein-coding nucleotides lie in a meta-domain, and 67.9% of pathogenic or likely pathogenic ClinVar missense variants in GRCh38 (37,692 of 55,548) fall at such a position. The authors show how MetaDome helped reclassify a de novo missense variant of uncertain significance in RALA, and identify 52,463 ClinVar missense variants of uncertain significance for which meta-domains supply otherwise unavailable pathogenic evidence.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Preprint, not peer reviewed. For a tool already used in routine practice, the value of this release lies in GRCh38 support and incremental updates, which keep a guideline-cited resource from becoming outdated. The figure of 52,463 variants of uncertain significance refers to cases where evidence becomes available, not to demonstrated reclassifications: a single example, RALA, is reported, and the evidence strength to assign to meta-domains is not calibrated in the abstract.

Analysis by Dr Thibaut Benquey