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Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants

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Title: Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants
Authors: David, A
Khanna, T
Hanna, G
Sternberg, M
Item Type: Journal Article
Abstract: 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.
Issue Date: 1-May-2021
Date of Acceptance: 7-Dec-2020
URI: http://hdl.handle.net/10044/1/86131
DOI: 10.1007/s00439-020-02246-z
ISSN: 0340-6717
Publisher: Springer
Start Page: 805
End Page: 812
Journal / Book Title: Human Genetics
Volume: 140
Issue: 5
Copyright Statement: © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: WT/104955/Z/14/Z
BB/P023959/1
BB/P011705/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Genetics & Heredity
0604 Genetics
1104 Complementary and Alternative Medicine
1114 Paediatrics and Reproductive Medicine
Publication Status: Published
Open Access location: https://doi.org/10.1007/s00439-020-02246-z
Online Publication Date: 2021-01-27
Appears in Collections:Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons