バリアントの機能予測ツールのリスト

  • American College of Medical Genetics and GenomicsとAssociation for Molecular Pathologyからの提案として、メンデル遺伝病のバリアントの病原性を5段階評定しよう、というものがありました
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(論文へのリンク)
  • メンデル遺伝病が疑われるケースでシークエンスをすると、バリアントが見つかるわけですが、そのすべてが病気の原因になっているとは限りません。集団に広く分布している「非病原性バリアント」かもしれないし、個人がたまたまレアバリアントとして持っているかもしれないし。
  • そのあたりの解決のためには、表現型とシークエンスデータを登録して相互参照する必要があるし、バリアントの機能予測も欠かせません。(このデータベースのテーブルが、この論文のテーブル1)
  • これはメンデル遺伝病とそれに類するいわゆる「単一遺伝子病」のpathogenic variantsに関する提案であって、ファーマコジェノミクス、複合遺伝性疾患、体細胞変異は対象外です。
  • Variants
    • 変異・多型・バリアントなど呼称はいろいろだが、バリアント(variant)で統一
  • その病原性に関する情報をpathogenic, likely pathogenic, uncertain significance, likely benign, benignの5段階とする
  • ただし"likely"の定義は不完全
  • 以下、その論文にテーブル化されていた機能予測ツールの一覧(テーブル2)とリンクです
  • In silico pathogenicity prediction algorithms/tools
    • Missense Prediction
      • Consurf
        • Server for the Identification of Functional Regions in Proteins
      • FATHMM
        • Functional Analysis through Hidden Markov Models
      • MutationAssessor
        • predicts the functional impact of amino-acid substitutions in proteins
      • PANTHER
        • Estimates the likelihood of a particular nonsynonymous (amino-acid changing) coding SNP to cause a functional impact on the protein
      • PhD-SNP
        • Predictor of human Deleterious Single Nucleotide Polymorphisms
      • SIFT
        • predicts whether an amino acid substitution affects protein function.
      • SNPs&GO
        • Predicting disease associated variations using GO terms
      • AlignGVGD
        • combines the biophysical characteristics of amino acids and protein multiple sequence alignments to predict where missense substitutions in genes of interest fall in a spectrum from enriched delterious to enriched neutral
      • MAPP
        • the physicochemical variation present in a column of a protein sequence alignment and, on the basis of this variation, predicts the impact of all possible amino acid substitutions on the function of the protein.
      • MutationTaster2
        • the pathogenic potential of DNA sequence alterations. It is designed to predict the functional consequences of not only amino acid substitutions but also intronic and synonymous alterations, short insertion and/or deletion (indel) mutations and variants spanning intron-exon borders.
      • MutPred
        • classify an amino acid substitution as disease-associated or neutral in human. In addition, it predicts molecular cause of disease
      • PolyPhen2
        • predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations
      • PROVEAN
        • predicts whether an amino acid substitution or indel has an impact on the biological function of a protein.
      • nsSNPAnalyzer
        • predict whether a nonsynonymous single nucleotide polymorphism (nsSNP) has a phenotypic effect. also provides additional information about the SNP to facilitate the interpretation of results, e.g., structural environment and multiple sequence alignment
      • Condel
        • Condel is a method to assess the outcome of non-synonymous SNVs using a CONsensus DELeteriousness score that combines various tools (MutationAssessor, FATHMM).
      • CADD
        • scoring the deleteriousness of single nucleotide variants as well as insertion/deletions variants in the human genome.
    • Splice site prediction
      • GeneSplicer
        • detecting splice sites in the genomic DNA of various eukaryotes
      • Human Splicing Finder3
        • calculate the consensus values of potential splice sites and search for branch points, new algorithms were developed. Furthermore, we have integrated all available matrices to identify exonic and intronic motifs, as well as new matrices to identify hnRNP A1, Tra2-β and 9G8.
      • MaxEntScan
        • modeling the sequences of short sequence motifs such as those involved in RNA splicing which simultaneously accounts for non-adjacent as well as adjacent dependencies between positions; predicting splicing mutations
      • NetGene2
        • producing neural network predictions of splice sites in human, C. elegans and A. thaliana DNA
      • NNSplice
        • A neural network based program to find possible 5' and 3' splice sites.
      • FSPLICE (URL 機能せず)
    • Nucleotide conservation prediction
      • GERP
        • identifies constrained elements in multiple alignments by quantifying substitution deficits. These deficits represent substitutions that would have occurred if the element were neutral DNA, but did not occur because the element has been under functional constraint.
      • Phast(PhastConsとPhastPとを含む)
        • consists of about half a dozen major programs, plus more than a dozen utilities for manipulating sequence alignments, phylogenetic trees, and genomic annotations (see left panel). For the most part, PHAST focuses on two kinds of applications: the identification of novel functional elements, including protein-coding exons and evolutionarily conserved sequences; and statistical phylogenetic modeling, including estimation of model parameters, detection of signatures of selection, and reconstruction of ancestral sequences.