UniProt Genomic Mapping for Deciphering Functional Effects of Missense Variants

Abstract Understanding the association of genetic variation with its functional consequences in proteins is essential for the interpretation of genomic data and identifying causal variants in diseases. Integration of protein function knowledge with genome annotation can assist in rapidly comprehending genetic variation within complex biological processes. Here, we describe mapping UniProtKB human sequences and positional annotations such as active sites, binding sites, and variants to the human genome (GRCh38) and the release of a public genome track hub for genome browsers. To demonstrate the power of combining protein annotations with genome annotations, we present specific biological examples in disease-related genes and proteins;illustrating how the combination of protein and genome annotations helps the functional interpretation of variants. Computational comparisons of UniProtKB annotations and protein variants with ClinVar clinically annotated SNP data show that 32% of UniProtKB variants collate with 8% of ClinVar SNPs. The majority of co-located UniProtKB disease-associated variants (86%)map to ‘pathogenic’ ClinVar SNPs. UniProt and ClinVar are collaborating to provide a unified clinical variant annotation for genomic, protein and clinical researchers. The genomic track hubs are downloadable from the UniProt FTP site and discoverable as public track hubs at the UCSC and Ensembl genome browsers.