Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.
Hashem A. Shihab,Julian Gough,David Neil Cooper,Peter D. Stenson,Gary L A Barker,Keith J. Edwards,Ian N. M. Day,Tom R. Gaunt +7 more
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TLDR
The Functional Analysis Through Hidden Markov Models (FATHMM) software and server is described: a species‐independent method with optional species‐specific weightings for the prediction of the functional effects of protein missense variants, demonstrating that FATHMM can be efficiently applied to high‐throughput/large‐scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations.Abstract:
The rate at which nonsynonymous single nucleotide polymorphisms (nsSNPs) are being identified in the human genome is increasing dramatically owing to advances in whole-genome/whole-exome sequencing technologies. Automated methods capable of accurately and reliably distinguishing between pathogenic and functionally neutral nsSNPs are therefore assuming ever-increasing importance. Here, we describe the Functional Analysis Through Hidden Markov Models (FATHMM) software and server: a species-independent method with optional species-specific weightings for the prediction of the functional effects of protein missense variants. Using a model weighted for human mutations, we obtained performance accuracies that outperformed traditional prediction methods (i.e., SIFT, PolyPhen, and PANTHER) on two separate benchmarks. Furthermore, in one benchmark, we achieve performance accuracies that outperform current state-of-the-art prediction methods (i.e., SNPs&GO and MutPred). We demonstrate that FATHMM can be efficiently applied to high-throughput/large-scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations. To illustrate this, we evaluated nsSNPs in wheat (Triticum spp.) to identify some of the important genetic variants responsible for the phenotypic differences introduced by intense selection during domestication. A Web-based implementation of FATHMM, including a high-throughput batch facility and a downloadable standalone package, is available at http://fathmm.biocompute.org.uk.read more
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Whole Exome Sequencing with Comprehensive Gene Set Analysis Identified a Biparental-Origin Homozygous c.509G>A Mutation in PPIB Gene Clustered in Two Taiwanese Families Exhibiting Fetal Skeletal Dysplasia during Prenatal Ultrasound.
Ting-Yu Chang,I-Fang Chung,Wan-Ju Wu,Shun-Ping Chang,Wen-Hsiang Lin,Norman A. Ginsberg,Gwo-Chin Ma,Ming Chen +7 more
TL;DR: The use of trio-based whole exome sequencing with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy supports a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirms that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies.
Journal ArticleDOI
Identification of altered biological processes in heterogeneous RNA-sequencing data by discretization of expression profiles.
Andrea Lauria,Serena Peirone,Marco Del Giudice,Francesca Priante,Prabhakar Rajan,Prabhakar Rajan,Michele Caselle,Salvatore Oliviero,Matteo Cereda +8 more
TL;DR: GSECA showed that, in prostate cancer, PTEN loss appears to establish an immunosuppressive tumor microenvironment through the activation of STAT3, and low PTEN expression levels have a detrimental impact on patient disease-free survival.
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Syndromic hearing loss molecular diagnosis: Application of massive parallel sequencing.
Yasmin Soares de Lima,Marcela A. Chiabai,Jun Shen,Mara Santos Córdoba,Beatriz R. Versiani,Rosenelle Oliveira Araújo Benício,Robert Pogue,Regina Célia Mingroni-Netto,Karina Lezirovitz,Aline Pic-Taylor,Juliana F. Mazzeu,Silviene Fabiana de Oliveira +11 more
TL;DR: A customized Ion AmpliSeq Panel was customized to cover the coding sequences of 52 genes, and demonstrated effectiveness in molecular diagnosis when compared to others in the literature, especially for patients with a defined clinical diagnosis.
Journal ArticleDOI
Vanno: A visualization-aided variant annotation tool
Po-Jung Huang,Chi-Ching Lee,Bertrand Chin-Ming Tan,Yuan Ming Yeh,Kuo-Yang Huang,Ruei Chi Gan,Ting-Wen Chen,Cheng Yang Lee,Sheng Ting Yang,Chung-Shou Liao,Hsuan Liu,Petrus Tang +11 more
TL;DR: Vanno, a Web‐based application for in‐depth analysis and rapid evaluation of disease‐causative genome sequence alterations, is developed, providing a complete solution for targeted and exome sequencing analysis.
Journal ArticleDOI
CancerVar: An artificial intelligence–empowered platform for clinical interpretation of somatic mutations in cancer
TL;DR: CancerVar is developed to facilitate automated and standardized interpretations for 13 million somatic mutations based on the AMP/ASCO/CAP 2017 guidelines and introduced a deep learning framework to predict oncogenicity for these variants using both functional and clinical features.
References
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