Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Bioinformatics. 2021 Apr 1;36(22-23):5448-5455. doi: 10.1093/bioinformatics/btaa1008.
When rare missense variants are clinically interpreted as to their pathogenicity, most are classified as variants of uncertain significance (VUS). Although functional assays can provide strong evidence for variant classification, such results are generally unavailable. Multiplexed assays of variant effect can generate experimental 'variant effect maps' that score nearly all possible missense variants in selected protein targets for their impact on protein function. However, these efforts have not always prioritized proteins for which variant effect maps would have the greatest impact on clinical variant interpretation.
Here, we mined databases of clinically interpreted variants and applied three strategies, each building on the previous, to prioritize genes for systematic functional testing of missense variation. The strategies ranked genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movability- and reappearance-weighted impact scores, to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to account for the more resource-intensive nature of generating variant effect maps for longer genes. Our results could be used to guide systematic functional testing of missense variation toward greater impact on clinical variant interpretation.
Source code available at: https://github.com/rothlab/mave-gene-prioritization.
Supplementary data are available at Bioinformatics online.
当罕见的错义变异被临床解释为致病性时，大多数被归类为意义不明的变异（VUS）。虽然功能测定可以为变异分类提供有力证据，但这些结果通常无法获得。变异效应的多重分析可以生成实验性的“变异效应图谱”，对选定蛋白靶标中的几乎所有可能的错义变异进行评分，以评估其对蛋白功能的影响。然而，这些努力并没有始终优先考虑那些对临床变异解释有最大影响的变异效应图谱的蛋白。
在这里，我们挖掘了临床解释变异的数据库，并应用了三种策略，每种策略都在前一种策略的基础上，对系统地进行错义变异功能测试的基因进行优先级排序。这些策略按以下标准对基因进行排序：(i) 根据已向 ClinVar 报告的独特错义 VUS 的数量；(ii) 根据可移动性和重现加权影响评分，为重现、可移动的 VUS 赋予额外权重；(iii) 根据难度调整的影响评分，考虑到为更长的基因生成变异效应图谱需要更多的资源。我们的结果可用于指导对错义变异进行系统的功能测试，以更大程度地影响临床变异解释。
可在 https://github.com/rothlab/mave-gene-prioritization 上获得源代码。
补充数据可在 Bioinformatics 在线获得。
