KVarPredDB: a database for predicting pathogenicity of missense sequence variants of keratin genes associated with genod
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PRIMARY RESEARCH
Open Access
KVarPredDB: a database for predicting pathogenicity of missense sequence variants of keratin genes associated with genodermatoses Yuyi Ying1,2†, Lu Lu1,2†, Santasree Banerjee3†, Lizhen Xu4, Qiang Zhao1,2, Hao Wu1,2, Ruiqi Li5, Xiao Xu1,2, Hua Yu4, Dante Neculai4, Yongmei Xi1,2, Fan Yang4, Jiale Qin6* and Chen Li1,2*
Abstract Background: Germline variants of ten keratin genes (K1, K2, K5, K6A, K6B, K9, K10, K14, K16, and K17) have been reported for causing different types of genodermatoses with an autosomal dominant mode of inheritance. Among all the variants of these ten keratin genes, most of them are missense variants. Unlike pathogenic and likely pathogenic variants, understanding the clinical importance of novel missense variants or variants of uncertain significance (VUS) is the biggest challenge for clinicians or medical geneticists. Functional characterization is the only way to understand the clinical association of novel missense variants or VUS but it is time consuming, costly, and depends on the availability of patient’s samples. Existing databases report the pathogenic variants of the keratin genes, but never emphasize the systematic effects of these variants on keratin protein structure and genotype-phenotype correlation. Results: To address this need, we developed a comprehensive database KVarPredDB, which contains information of all ten keratin genes associated with genodermatoses. We integrated and curated 400 reported pathogenic missense variants as well as 4629 missense VUS. KVarPredDB predicts the pathogenicity of novel missense variants as well as to understand the severity of disease phenotype, based on four criteria; firstly, the difference in physicochemical properties between the wild type and substituted amino acids; secondly, the loss of inter/intra-chain interactions; thirdly, evolutionary conservation of the wild type amino acids and lastly, the effect of the substituted amino acids in the heptad repeat. Molecular docking simulations based on resolved crystal structures were adopted to predict stability changes and get the binding energy to compare the wild type protein with the mutated one. We use this basic information to determine the structural and functional impact of novel missense variants on the keratin coiled-coil heterodimer. KVarPredDB was built under the integrative web application development framework SSM (SpringBoot, Spring MVC, MyBatis) and implemented in Java, Bootstrap, React-mutation-mapper, (Continued on next page)
* Correspondence: [email protected]; [email protected] † Yuyi Ying, Lu Lu and Santasree Banerjee contributed equally to this work. 6 Department of Ultrasound, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China 1 Department of Human Genetics, and Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 Internatio
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