Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants.
Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants.
复制标题
DOI：
10.1007/s00439-020-02246-z
复制
发表时间：
2021-05
期刊：
影响因子：
5.3
通讯作者：
David A
中科院分区：
文献类型：
--
作者：
Khanna T;Hanna G;Sternberg MJE;David A
人类遗传变异的解释是现代遗传学的最大挑战之一。迫切需要新的方法来优先考虑变异，特别是那些罕见或缺乏明确临床解释的变异。我们检查了来自GnomAD、ClinVar和UniProt的10，136，597种人类错义遗传变异。我们能够对这些变体中的3，960，015个进行大规模的基于原子的映射和表型解释，以获得18，874个实验和84，818个内部预测的人类蛋白质组的三维坐标。我们证明，GnomAD数据库中14%的氨基酸取代可以进行结构分析，预计会影响蛋白质结构（n = 568，548，其中566，439罕见或极其罕见），因此可能具有未知的致病作用。ClinVar数据库中报告的19.0%（n = 6266）临床意义未知或解释冲突的变异体也是如此。结构分析的结果可在专用网络目录Missense 3D-DB（http：//missense3d.bc.ic.ac.uk/）中获得。对于4个M变体中的每一个，结构分析的结果以友好简洁的格式呈现，可以包括在临床遗传报告中。结构分析的详细报告也可供结构生物学的非专家使用。纳入了SIFT和PolyPhen的群体频率和预测，以进行更全面的变异解释。这是人类遗传变异的第一个大规模基于原子的结构解释，为遗传学家和生物医学界提供了一种新的遗传变异解释方法。本文的在线版本（10.1007/s 00439 -020-02246-z）包含补充材料，可供授权用户使用。
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. The online version of this article (10.1007/s00439-020-02246-z) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
14.9
作者：
Schymkowitz J;Borg J;Stricher F;Nys R;Rousseau F;Serrano L
通讯作者：
Serrano L
影响因子：
30.8
作者：
Havrilla, James M.;Pedersen, Brent S.;Quinlan, Aaron R.
通讯作者：
Quinlan, Aaron R.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
5.3
作者：
Lelieveld SH;Veltman JA;Gilissen C
通讯作者：
Gilissen C