Motivation: Unambiguous variant descriptions are of utmost importance in clinical genetic diagnostics, scientific literature and genetic databases. The Human Genome Variation Society (HGVS)... Show moreMotivation: Unambiguous variant descriptions are of utmost importance in clinical genetic diagnostics, scientific literature and genetic databases. The Human Genome Variation Society (HGVS) publishes a comprehensive set of guidelines on how variants should be correctly and unambiguously described. We present the implementation of the Mutalyzer 2 tool suite, designed to automatically apply the HGVS guidelines so users do not have to deal with the HGVS intricacies explicitly to check and correct their variant descriptions.Results: Mutalyzer is profusely used by the community, having processed over 133 million descriptions since its launch. Over a five year period, Mutalyzer reported a correct input in similar to 50% of cases. In 41% of the cases either a syntactic or semantic error was identified and for similar to 7% of cases, Mutalyzer was able to automatically correct the description. Show less
BACKGROUND The use of a standard human sequence variant nomenclature is advocated by the Human Genome Variation Society in order to unambiguously describe genetic variants in databases and... Show moreBACKGROUND The use of a standard human sequence variant nomenclature is advocated by the Human Genome Variation Society in order to unambiguously describe genetic variants in databases and literature. There is a clear need for tools that allow the mining of data about human sequence variants and their functional consequences from databases and literature. Existing text mining focuses on the recognition of protein variants and their effects. The recognition of variants at the DNA and RNA levels is essential for dissemination of variant data for diagnostic purposes. Development of new tools is hampered by the complexity of the current nomenclature, which requires processing at the character level to recognize the specific syntactic constructs used in variant descriptions. RESULTS We approached the gene variant nomenclature as a scientific sublanguage and created two formal descriptions of the syntax in Extended Backus-Naur Form: one at the DNA-RNA level and one at the protein level. To ensure compatibility to older versions of the human sequence variant nomenclature, previously recommended variant description formats have been included. The first grammar versions were designed to help build variant description handling in the Alamut mutation interpretation software. The DNA and RNA level descriptions were then updated and used to construct the context-free parser of the Mutalyzer 2 sequence variant nomenclature checker, which has already been used to check more than one million variant descriptions. CONCLUSIONS The Extended Backus-Naur Form provided an overview of the full complexity of the syntax of the sequence variant nomenclature, which remained hidden in the textual format and the division of the recommendations across the DNA, RNA and protein sections of the Human Genome Variation Society nomenclature website (http://www.hgvs.org/mutnomen/). This insight into the syntax of the nomenclature could be used to design detailed and clear rules for software development. The Mutalyzer 2 parser demonstrated that it facilitated decomposition of complex variant descriptions into their individual parts. The Extended Backus-Naur Form or parts of it can be used or modified by adding rules, allowing the development of specific sequence variant text mining tools and other programs, which can generate or handle sequence variant descriptions. Show less
ABSTRACT : As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease... Show moreABSTRACT : As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specific purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-file record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)-approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants affecting human health. Further information can be found on the LRG web site: http://www.lrg-sequence.org. Show less
ABSTRACT : As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease... Show moreABSTRACT : As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specific purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-file record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)-approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants affecting human health. Further information can be found on the LRG web site: http://www.lrg-sequence.org. Show less
