Prot2HG

Prot2HG maps protein domain annotations onto the human reference genome hg19 to identify whether DNA variants intersect annotated protein residues and conserved functional domains.

Key Features:

• Variant Mapping: Prot2HG translates chromosomal coordinates to protein residues and determines whether DNA variants lie within annotated conserved functional protein domains.
• Multiple-Site Query Capability: Prot2HG supports queries of multiple genomic sites simultaneously.
• Integration with GENESIS Platform: Prot2HG annotations are incorporated into the GENESIS platform enabling queries across nearly 8,000 exomes and genomes from families with rare Mendelian disorders.

Scientific Applications:

• Variant Prioritization: Annotation of coding genome variants onto conserved protein domains to inform prioritization based on potential functional impact.
• Rare vs. Common Variant Analysis: Analyses showed rare (<1%) variants are significantly more likely to be annotated onto a protein domain than common (>1%) variants.
• ClinVar Pathogenicity Correlation: Variants classified as pathogenic or likely pathogenic in ClinVar have a higher likelihood of mapping onto protein domains.
• Epileptic Encephalopathy Cohort: In a cohort of patients with epileptic encephalopathy, 71% (43 of 60) of causal variants were mapped onto protein domains.

Methodology:

Protein data were retrieved from the National Center for Biotechnology Information using Entrez Programming Utilities; human protein domains were processed to reverse-translate residue positions and map them to hg19 coordinates, producing a dataset of 760,487 protein domains from 42,371 protein models stored in a MySQL database.