title: UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution.
abstract: Whole-exome sequencing (WES) is increasingly applied to research and clinical diagnosis of human diseases. It typically results in large amounts of genetic variations. Depending on the mode of inheritance, only one or two correspond to pathogenic mutations responsible for the disease and present in affected individuals. Therefore, it is crucial to filter out nonpathogenic variants and limit downstream analysis to a handful of candidate mutations. We have developed a new computational combinatorial system UMD-Predictor (http://umd-predictor.eu) to efficiently annotate cDNA substitutions of all human transcripts for their potential pathogenicity. It combines biochemical properties, impact on splicing signals, localization in protein domains, variation frequency in the global population, and conservation through the BLOSUM62 global substitution matrix and a protein-specific conservation among 100 species. We compared its accuracy with the seven most used and reliable prediction tools, using the largest reference variation datasets including more than 140,000 annotated variations. This system consistently demonstrated a better accuracy, specificity, Matthews correlation coefficient, diagnostic odds ratio, speed, and provided the shortest list of candidate mutations for WES. Webservices allow its implementation in any bioinformatics pipeline for next-generation sequencing analysis. It could benefit to a wide range of users and applications varying from gene discovery to clinical diagnosis.
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: David
authors: D
authors: Salgado
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: Jean-Pierre
authors: JP
authors: Desvignes
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: Ghadi
authors: G
authors: Rai
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: Arnaud
authors: A
authors: Blanchard
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: Morgane
authors: M
authors: Miltgen
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: Amélie
authors: A
authors: Pinard
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.|APHM, Hôpital TIMONE Enfants, Laboratoire de Génétique Moléculaire, Marseille 13385, France.
authors: Nicolas
authors: N
authors: Lévy
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.
authors: Gwenaëlle
authors: G
authors: Collod-Béroud
authors: Aix-Marseille Université, GMGF, Marseille 13385, France.|Inserm, UMR_S 910, Marseille 13385, France.|APHM, Hôpital TIMONE Enfants, Laboratoire de Génétique Moléculaire, Marseille 13385, France.
authors: Christophe
authors: C
authors: Béroud
mesh_terms: D000465:Algorithms; D019943:Amino Acid Substitution; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D059472:Exome; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D017354:Point Mutation; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: NGS; bioinformatics; mutation; nonsense; nonsynonymous; pathogenicity prediction; substitution; synonymous