Nomenclature for the description of sequence variationsJ.T. den Dunnen, S.E. Antonarakis: Hum Genet 109(1): 121-124, 2001Reproduced with kind permission from Prof. S. E. Antonarakis(last modified March 7, 2001)Questions and comments regarding nomenclature should be directed to Professor Stylianos Antonarakis (stylianos.antonarakismedecine.unige.ch) or Dr. Johan T. den Dunnen (ddunnenlumc.nl). This page can also be found at theHGVSsite.Contents Introduction Recommendationso Generalo DNA-levelo RNA-levelo protein-level Codons and encoded amino acidso genetic codeo amino acid descriptions(one / three letter code)IntroductionRecently, a nomenclature system has been suggested for the description of changes (mutations and polymorphisms) in DNA and protein sequences Antonarakis, S.E. and the Nomenclature Working Group(1998)Recommendations for a nomenclature system for human gene mutations.Hum.Mut. 11: 1-3. These nomenclature recommendations have now been largely accepted and stimulated the uniform and unequivocal description of sequence changes. However, current rules do not yet cover all types of mutations, nor do they cover more complex mutations. This document lists the existing recommendations and summarizes suggestions for the description of additional, more complex changes, (shown in italics) based on a manuscript published in Human Mutation den Dunnen, JT and Antonarakis, SE(2000).Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.Hum.Mut. 15: 7-12 (copy in PDF format).Discussions regarding the advantages and disadvantages of the suggestions are necessary in order to continuously improve the designation of sequence changes. The consensus of the discussions will be posted here and we invite investigators to communicate with us regarding these suggestions. Furthermore, we invite investigators to send us complicated cases not covered yet, with a suggestion of how to describe these (mail toddunnenlumc.nl and Stylianos.Antonarakismedecine.unige.ch). We hope these pages will be used as a guide to describe any sequence change, ultimately evolving into a uniformly accepted reference for mutation nomenclature description.General recommendations(suggestions extending the current recommendations are in italtics)The termsequence variationis used to prevent confusion with the termsmutationandpolymorphism, mutation meaning change in some disciplines and disease-causing change in others and polymorphism meaning non disease-causing change or change found at a frequency of 1% or higher in the population.The basic recommendation is to usesystematic namesto describe each sequence variation. For this, variations are described at the most basic level, i.e. the DNA level, using either a genomic or a cDNA reference sequence. A genomic reference sequence is preferred because it overcomes difficult cases, including multiple transcription initiation sites (promoters), alternative splicing, the use of different poly-A addition signals, multiple translation initiation sites (ATG-codons) and the occurence of length variations. When, like in most cases, the entire genomic sequence is not known, a cDNA reference sequence should be used instead. sequence variations are described in relation to a reference sequence for which the accession number from a primary sequence database (Genbank, EMBL, DDJB, SWISS-PROT) should be mentioned in the publication/database submission (e.g. M18533) tabular listings of the sequence variations described should contain columns for DNA, RNA and protein and clearly indicate whether the changes wereexperimentally determinedor only theoretically deduced to avoid confusion in the description of a sequence change, preceed the description with a letter indicating the type of reference sequence used;o g. for agenomicsequence (e.g. g.76AT)o c. for acDNAsequence (e.g. c.76AT)o m. for amitochondrialsequence (e.g. m.76AT)(from David Fung, Camperdown, Australia)o r. for anRNAsequence (e.g. r.76au)o p. for aproteinsequence (e.g. p.K76A) to discrimintate between the different levels (DNA, RNA or protein), descriptions are unique;o at DNA-level, in capitals, starting with a number refering to the first nucleotide affected (e.g. c.76AT)o at RNA-level, in lower-case, starting with a number refering to the first nucleotide affected (e.g. r.76au)o at protein level, in capitals, starting with a letter referring to first the amino acid (one-letter code) affected (e.g. p.T26P) a range of affected residues is indicated by a _-character (underscore) separating the first and last residue affected (e.g. 76_78delACT)NOTE:current recommendations use the -character (i.e. 76-78delACT) for deletions, duplications or insertions in short tandem repeats, the most 3 nucleotide is arbitrarily assigned as the nucleotide changed