Protein domains provide a new layer of information for classifying human variations in rare diseases

Abstract

Introduction: Using the ACMG-AMP guidelines for the interpretation of sequence variants, it remains difficult to meet the criterion associated with the protein domain, PM1, which is assigned in only about 10% of cases, whereas the criteria related to variant frequency, PM2/BA1/BS1, is reported in 50% of cases. To improve the classification of human missense variants using protein domains information, we developed the DOLPHIN system (https://dolphin.mmg-gbit.eu).Methods: We used Pfam alignments of eukaryotes to define DOLPHIN scores to identify protein domain residues and variants that have a significant impact. In parallel, we enriched gnomAD variants frequencies for each domains’ residue. These were validated using ClinVar data.Results: We applied this method to all potential human transcripts’ variants, resulting in 30.0% being assigned a PM1 label, whereas 33.2% were eligible for a new benign support criterion, BP8. We also showed that DOLPHIN provides an extrapolated frequency for 31.8% of the variants, compared to the original frequency available in gnomAD for 7.6% of them.Discussion: Overall, DOLPHIN allows a simplified use of the PM1 criterion, an expanded application of the PM2/BS1 criteria and the creation of a new BP8 criterion. DOLPHIN could facilitate the classification of amino acid substitutions in protein domains that cover nearly 40% of proteins and represent the sites of most pathogenic variants.

A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria

“…The gene is highly intolerant to missense variants (gnomAD Z = 6.01) and contains subdomains (DUF1394 and FragX_IP) that are tightly interlocked at the CYFIP2‐WAVE1 interface. The p.(Val551Leu) variant is present in the conserved FragX_IP subdomain of CYFIP2, and further confirmed by the bioinformatics tool Domain Logo Protein for Human Information (DOLPHIN) to be located in a functional domain affecting a key residue (WT: 2.265; ∆: −6.45) (Corcuff et al, 2023). It is absent from all databases (gnomAD, TopMed, All‐of‐Us), highly conserved across species (GERP_RS: 5.63; phyloP100: 9.947) and predicted deleterious (CADD: 27; MutationTaster: D).…”

The importance of protein domain mutations in cancer therapy

“…Zinc finger domain mutations disrupt gene regulation, promoting cancer [ 41 ]. These mutations underscore the intricate nature of cancer genetics and underscore the critical need for personalized treatments in the ongoing pursuit of better cancer therapies and outcomes [ 42 ]. Understanding their effects can inspire new treatments.…”