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Nomenclature for the description of sequence
variations
J.T. den Dunnen, S.E. Antonarakis: Hum Genet 109(1):
121-124, 2001
Reproduced 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.antonarakis@medecine.unige.ch
) or Dr. Johan T. den Dunnen ( ddunnen@lumc.nl
). This page can also be found at the HGVS site.
Contents
Introduction
Recently, 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 to ddunnen@lumc.nl and Stylianos.Antonarakis@medecine.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 term "sequence variation" is used to prevent
confusion with the terms "mutation" and "polymorphism",
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 use systematic names to
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 were experimentally
determined or 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;
- "g."
for a genomic sequence (e.g. g.76A>T)
- "c."
for a cDNA sequence (e.g. c.76A>T)
- "m."
for a mitochondrial sequence (e.g. m.76A>T) (from David Fung, Camperdown, Australia)
- "r."
for an RNA sequence (e.g. r.76a>u)
- "p."
for a protein sequence (e.g. p.K76A)
- to
discrimintate between the different levels (DNA, RNA or protein),
descriptions are unique;
- at
DNA-level, in capitals, starting with a number refering to the first
nucleotide affected (e.g. c.76A>T)
- at
RNA-level, in lower-case, starting with a number refering to the first
nucleotide affected (e.g. r.76a>u)
- 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
- two sequence variations in one allele are listed between brackets, separated
by a "+"-character (e.g. [76A>C + 83G>C])
NOTE: current recommendations use the ";"-character as a
separator (i.e. [76A>C;
83G>C])
- sequence
changes in different alleles (e.g. for recessive diseases) are listed
between brackets, separated by a "+"-character (e.g. [76A>C] + [87delG])
NOTE: the current recommendation is [76A>C + 87delG]
- a unique
identifier should be assigned to each mutation. The unique OMIM-identifier
can be used, otherwise database curators should assign unique identifiers
DNA level
- nucleotides are designated
by the bases (in upper case); A (adenine), C (cytosine), G (guanine) and T
(thymidine)
- nucleotide numbering;
- nucleotide +1 is the A of
the ATG-translation initiation codon, the nucleotide 5' to +1 is numbered
-1; there is no base 0
- non-coding regions;
- the nucleotide 5' of the
ATG-translation initiation codon is -1
- the nucleotide 3' of
the translation termination codon is *1
- intronic
nucleotides;
- beginning of the
intron: the number of the last
nucleotide of the preceeding exon, a plus sign and the position in the
intron, e.g. 77+1G,
77+2T (when the exon number is known, the notation can also be described
as IVS1+1G,
IVS1+2T)
- end of the intron: the number of the first nucleotide of the
following exon, a minus sign and the position upstream in the intron,
e.g. 78-2A,
78-1G (when the exon
number is known, the notation can also be described as IVS1-2A, IVS1-2G)
- for deletions, duplications
or insertions in single nucleotide (or amino acid) stretches or tandem
repeats, the most 3' copy is arbitrarily assigned to have been changed
(e.g. ACTTTGTGCC to ACTTTGCC is described as 7_8delTG)
Description of nucleotide changes
- substitutions are
designated by a “>”-character
- 76A>C denotes that at nucleotide 76 a A is changed to a C
- 88+1G>T (alternatively IVS2+1G>T) denotes the G to T
substitution at nucleotide +1of intron 2, relative to the cDNA positioned
between nucleotides 88 and 89
- 89-2A>C (alternativelyIVS2-2A>C) denotes the A to C
substitution at nucleotide -2 of intron 2, relative to the cDNA
positioned between nucleotides 88 and 89
NOTE: polymorphic
variants are sometimes described as 76A/G, but this is not recommened !
- deletions are designated by "del"
after the nucleotide(s) flanking the deletion site
- 76_78del
(alternatively 76_78delACT) denotes a ACT deletion from nucleotides 76 to
78
- 82_83del
(alternatively 82_83delTG) denotes a TG deletion in the sequence ACTTTGTGCC
(A is nucleotide 76) to ACTTTGCC
- IVS2_IVS5del
(alternatives 88+?_923+? or EX3_5del) denotes an exonic deletion starting
at an unknown position in intron 2 (after nucleotide 88) and ending at an
unknown position in intron 5 (after nucleotide 923)
- insertions are
designated by "ins" after the
nucleotides flanking the insertion site, followed by the nucleotides
inserted
NOTE: as separator the "^"-character is sometimes used
but this is not recommened (e.g. 83^84insTG)
- 76_77insT
denotes that a T was inserted between nucleotides 76 and 77
- 83_84insTG
denotes a TG insertion in the TG-tandem repeat sequence of ACTTTGTGCC (A
is nucleotide 76) to ACTTTGTGTGCC. Note that this sequence
variation (a duplicating insertion) can also be described as a
duplication, i.e. 82_83dupTG (see "duplications")
- variability
of short sequence repeats, e.g.
in ACTGTGTGCC (A is nt 1991), are designated as 1993(TG)3-6 with
nucleotide 1993 containing the first TG-dinucleotide which is found
repeated 3 to 6 times in the population.
- insertion/deletions
(indels) are descibed
as a deletion followed by an insertion after the nucleotides afected
- 112_117delinsTG
(alternatively 112_117delAGGTCAinsTG or 112_117>TG) denotes the
replacement of nucleotides 112 to 117 (AGGTCA) by TG
- duplications are designated by "dup" after the nucleotides flanking the
duplication site,
- 77_79dupCTG
denotes that the nucleotides 77 to 79 were duplicated
- duplicating
insertions in short tandem repeats (or single nucleotide stretches) can
also be described as a duplication, e.g. a TG insertion in the TG-tandem
repeat sequence of ACTTTGTGCC (A is nt 76) to ACTTTGTGTGCC
can be described as 82_83dupTG (now 83_84insTG)
- inversions are designated by "inv" after the nucleotides flanking the
inversion site
- 203_506inv
(or 203_506inv304) denotes that the 304 nucleotides from position 203 to
506 have been inverted
- translocations (no suggestions yet)
- changes in
different alleles (e.g.
in recessive diseases) are described as "[change allele 1] + [change
allele 2]"
- [76A>C] + [76A>C] denotes a homozygous A to
C change at nucleotide 76
- [76A>C] + [?] denotes a A to C
change at nucleotide 76
in one allele and an unknown change in the other allele
- two
variations in one allele are described as "[first change + second change]"
- [76A>C + 83G>C] denotes an A to C change
at nucleotide 76 and a G to C change at nucleotide 83 in the same allele
NOTE: current
recommendations use the ";"-character as a separator (i.e. [76A>C; 83G>C])
RNA level
Sequence changes at RNA level are basically described as those at the DNA
level with the following modifications/additions;
- an “r.” is
used to indicate that a change is described at RNA-level
- nucleotides
are designated by the bases (in lower case); a (adenine), c (cytosine), g
(guanine) and u (uracil)
- 78u>a
denotes that at nucleotide 78
a U is changed to an A
- when one
change affects RNA-processing, yielding two or more transcripts, these are
described between square brackets, separated by a “;”-character
- [r.76a>c; r.76a>c +
r.73_88del] denotes the nucleotide change c.76A>C causing the appearance of
two RNA molecules, one carrying this variation only and one containing in
addition a deletion of nucleotides 73 to 88 (shift of the splice donor
site to within the exon)
- [r.=;
r.88_89ins88+1_88+10 + r.88+2t>c] denotes the intronic mutation
g.88+2T>C causing the appearance of two RNA molecules, one normal
(r.=) and one containing an insertion of the intronic nucleotides 88+1 to
88+10 with the nucleotide change 88+2t>c
- [r.88g>a +
r.88_89ins88+1_88+10] denotes the nucleotide change c.88G>A causing
an insertion of the intronic nucleotides 88+1 to 88+10 (shift of the
splice donor site to an intronic position)
Protein level
Sequence changes at protein level are basically described as those at the
DNA level with the following modifications/additions;
- the one letter amino acid code is used, with "X"
designating a translation termination codon
- Amino acid
numbering;
- the
translation initiator Methionine is numbered as +1
Description of amino acid changes
- substitutions;
- missense
changes
W26C denotes that
amino acid 26 (Tryptophan, W) is changed to a Cysteine (C)
- nonsense
changes
W26X denotes that amino
acid 26 (Tryptophan, W) is changed to a stop codon (X)
- initiating
methionine (M1)
Currently, mutations in the translation initiating Methionine (M1) are
mostly described as a substitution, e.g. M1V. This is not correct. Either
no protein is produced or the translation initiation site moves up- or
downstream. Unless experimental proof is available, it is probably best
to report the effect on protein level as “unknown”. When
experimental data show that no protein is made, the description "p.0"
might be most appropriate
NOTE: polymorphic
variants are sometimes described as 36L/I, but this is not recommened !
- deletions are designated by "del" after the nucleotide(s)
flanking the deletion site
- K29del in
the sequence CKMGHQQQCC (C is amino acid 28) denotes a
deletion of amino acid Lysine 29 (K) to CMGHQQQCC
- C28_M30del
denotes a deletion of three amino acids, from Cysteine 28 to Methionine
30
- Q35del in
the sequence CKMGHQQQCC (C is amino acid 28) denotes a
Glutamine 35 (Q) deletion to CKMGHQQCC
- if a
deletion creates a new amino acid at the deletion junction the change is
described as an insertion/deletions, e.g. C28_M30delinsW
(see below)
- insertions are
designated by "ins" after the nucleotides flanking the insertion
site, followed by the nucleotides inserted
NOTE: as separator the "^"-character is sometimes used
but this is not recommened (e.g. Q83^C84insQ)
- K29_M29insQSK
denotes that the sequence QSK was inserted between amino acids Lysine 29
(K) and Methionine 30 (M), changing CKMGHQQQCC (C is amino acid 28) to CKQSKMGHQQQCC
- Q35_C36insQ
in the sequence CKMGHQQQCC (C is amino acid 28) denotes a Glutamine (Q)
insertion to CKMGHQQQQCC. Note that this sequence variation
(a duplicating insertion) can also be described as a duplication, i.e.
Q35dup (see "duplications")
- if an
insertion creates a new amino acid at the insertion junction the change
is described as an insertion/deletions, e.g. C28delinsWV
(see below)
- variability
of short sequence repeats, e.g.
in CKMGHQQQCC (C is amino acid 28), are designated as 33(Q)3-6 with
amino acid Glutamine 33 (Q, the first repeated amino acid) found repeated
3 to 6 times in the population.
- insertion/deletions
(indels) are
described as a deletion followed by an insertion after the nucleotides
affected
- C28_K29delinsW
denotes a 3 bp deletion affecting the codons for Cysteine 28 and Lysine
29, substituting them for a codon for Tryptophan
- C28delinsWV
denotes a 3 bp insertion in the codon for Cysteine28, generating codons
for Tryptophan (W) and Valine (V)
- duplications are designated by "dup" after the amino acids flanking the
duplication site
- G31_Q33dup
in the sequence CKMGHQQQCC (C is amino acid 28) denotes a duplication of
amino acids Glycine 31 (G) to Glutamine 33 (Q) CKMGHQGHQQQCC
- duplicating
insertions in short tandem repeats (or single amino acid stretches) can
also be described as a duplication, e.g. a HQ insertion in the HQ-tandem
repeat sequence of CKMGHQHQCC (C is amino acid 28) to CKMGHQHQHQCC
can be described as H34_Q35dup (now Q35_C36insHQ)
- frame
shifting mutations; recommendations to describe these sequence changes have not yet been
made. Although it is probably not useful to add much detail in this
description, it might be sensible, e.g. in the case of C-terminal
mutations, to include the length of the new, shifted reading frame.
- R97fsX121
(alternative R97fs) denotes a frame shifting change with Arginine97 as
the first affected amino acid and the new reading frame being open for 23
amino acids
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