a catalog of biological databases
|Description:||The Missense3D portal hosts resources developed to characterise and prioritise missense variants (amino acid substitutions) using protein three-dimensional structural information from models or experimental coordinates.|
|University/Institution:||Centre for Integrative System Biology and Bioinformatics|
|Address:||Department of Life Sciences, Centre for Integrative System Biology and Bioinformatics, Imperial College London, London, SW7 2AZ, UK.|
|Contact name (PI/Team):||Alessia David|
|Contact email (PI/Helpdesk):||email@example.com|
Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants. [PMID: 33502607]
The interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt. We were able to perform large-scale atom-based mapping and phenotype interpretation of 3,960,015 of these variants onto 18,874 experimental and 84,818 in house predicted three-dimensional coordinates of the human proteome. We demonstrate that 14% of amino acid substitutions from the GnomAD database that could be structurally analysed are predicted to affect protein structure (n = 568,548, of which 566,439 rare or extremely rare) and may, therefore, have a yet unknown disease-causing effect. The same is true for 19.0% (n = 6266) of variants of unknown clinical significance or conflicting interpretation reported in the ClinVar database. The results of the structural analysis are available in the dedicated web catalogue Missense3D-DB ( http://missense3d.bc.ic.ac.uk/ ). For each of the 4 M variants, the results of the structural analysis are presented in a friendly concise format that can be included in clinical genetic reports. A detailed report of the structural analysis is also available for the non-experts in structural biology. Population frequency and predictions from SIFT and PolyPhen are included for a more comprehensive variant interpretation. This is the first large-scale atom-based structural interpretation of human genetic variation and offers geneticists and the biomedical community a new approach to genetic variant interpretation.