Table_1_VarQ: A Tool for the Structural and Functional Analysis of Human Protein Variants.XLSX

Understanding the functional effect of Single Amino acid Substitutions (SAS), derived from the occurrence of single nucleotide variants (SNVs), and their relation to disease development is a major issue in clinical genomics. Despite the existence of several bioinformatic algorithms and servers that predict if a SAS is pathogenic or not, they give little or no information at all on the reasons for pathogenicity prediction and on the actual predicted effect of the SAS on the protein function. Moreover, few actual methods take into account structural information when available for automated analysis. Moreover, many of these algorithms are able to predict an effect that no necessarily translates directly into pathogenicity. VarQ is a bioinformatic pipeline that incorporates structural information for the detailed analysis and prediction of SAS effect on protein function. It is an online tool which uses UniProt id and automatically analyzes known and user provided SAS for their effect on protein activity, folding, aggregation and protein interactions, among others. We show that structural information, when available, can improve the SAS pathogenicity diagnosis and more important explain its causes. We show that VarQ is able to correctly reproduce previous analysis of RASopathies related mutations, saving extensive and time consuming manual curation. VarQ assessment was performed over a set of previously manually curated RASopathies (diseases that affects the RAS/MAPK signaling pathway) related variants, showing its ability to correctly predict the phenotypic outcome and its underlying cause. This resource is available online at http://varq.qb.fcen.uba.ar/. Supporting Information & Tutorials may be found in the webpage of the tool.

深入探究单个氨基酸替换（SAS）的功能性影响，该影响源于单核苷酸变异（SNV）的发生，并探讨其与疾病发展的关联，是临床基因组学领域的一大课题。尽管已有众多生物信息学算法和服务器能够预测SAS是否具有致病性，但它们对于致病性预测的原因及SAS对蛋白质功能实际预测效果的信息提供甚少或根本无信息。此外，很少有实际方法在自动分析时考虑可用的结构信息。更进一步，许多算法能够预测出并不一定直接转化为致病性的效应。VarQ是一种生物信息学管道，它整合结构信息，以对SAS对蛋白质功能的影响进行详细分析和预测。该工具为在线工具，利用UniProt ID自动分析已知及用户提供的SAS对蛋白质活性、折叠、聚集以及蛋白质相互作用等方面的影响。研究表明，当结构信息可用时，可以改善SAS致病性诊断，并更重要的是解释其致病原因。研究表明，VarQ能够准确再现与RASopathies相关突变的前期分析，从而节省了大量的手动校对时间。VarQ评估在一系列先前手动校对的RASopathies（影响RAS/MAPK信号通路的疾病）相关变异上完成，展示了其正确预测表型结果及其潜在原因的能力。该资源可在http://varq.qb.fcen.uba.ar/在线获取。支持信息与教程可在该工具网页上找到。