Standards - definitions, symbols, nucleotides, codons, amino acids (v2.0)

Since references to WWW-sites are not yet acknowledged as citations, please mention den Dunnen JT and Antonarakis SE (2000). Hum.Mutat. 15:7-12 when referring to these pages.

Content

• definitions
• characters used
• nucleotides (DNA / RNA)
• genetic code
• amino acid descriptions  - one / three letter code

Definitions

for the description of sequence variants the following definitions are used

• substitution   =   a sequence change where one nucleotide is replaced by one other nucleotide
          NOTE:  a sequence change where one nucleotide is replaced by more then one other nucleotides is an delins (deletion-insertion)
          NOTE:  a sequence change where more then one nucleotides are replaced by one or more other nucleotides is a delins (deletion-insertion)
• deletion   =   a sequence change where one or more nucleotides are removed (deleted)
• duplication   =   a sequence change where a copy of one or more nucleotides are inserted directly 3'-flanking of the original copy
          NOTE:  when the copied sequence is not inserted directly 3'-flanking of the original copy the change is called an insertion
• insertion   =   a sequence change where one or more nucleotides are inserted between two original nucleotides but where the insertion is not a copy of a sequence immediately 5'-flanking (see duplication)
• inversion   =   a sequence change where more then one nucleotides replacing the original sequence are the reverse complement of the original sequence
• conversion   =   a sequence change where a range of nucleotides replacing the original sequence are a copy of a sequence elsewhere in the genome
• translocation   =   a sequence change where the sequence of one chromosome at the so called breakpoint (or junction) changes to that of another chromosome.
          NOTE:  a translocation occurs when 2 chromosomes break and the fragments rejoin to the another chromosome. A full description of a (reciprokal) translocation consists of 2 parts, one describing the first junction, the second describing the other junction (e.g. the chromosome 4;X junction as well as the chromosome X;4 junction).

Characters used

Below an overview of all different characters and signs used in the description of sequence variants with their meaning.

• reference sequences
  • c. = coding DNA reference sequence
  • g. = genomic reference sequence
  • m. = mitochondrial reference sequence
  • n. = non-coding RNA reference sequence (gene producing an RNA transcript but not a protein)
  • r.  = RNA reference sequence
  • p. = protein reference sequence
    
• diferent transcripts / protein isoforms generated from one gene
  • _v = specifies transcript variants in coding DNA variant descriptions (e.g. NM_000109.3(DMD_v2):c.4G>T)
  • _i = specifies protein isoforms in protein variant descriptions (e.g. NM_000109.3 (DMD_i2):p.Glu2*)
    
• numbering
  • genomic, mitochondrial, non-coding RNA, RNA and protein reference sequence
    • N = nucleotide N in reference sequence (e.g. 311A>G)
  • coding DNA reference sequence
    • N = nucleotide N in protein coding sequence (e.g. 11A>G)
    • -N = nucleotide N 5' of the ATG translation initiation codon (e.g. -4A>G)
      NOTE: so located in the 5'UTR or 5' of the transcription initiation site (upstream of the gene, incl. promoter)
    • *N = nucleotide N 3' of the translation stop codon (e.g. *6A>G)
      NOTE: so located in the 3'UTR or 3' of the polyA-addition site (incl.downstream of the gene)
    • N+M = nucleotide M in the intron after (3' of) position N in the coding DNA reference sequence (e.g. 30+4A>G)
    • N-M = nucleotide M in the intron before (5' of) position N in the coding DNA reference sequence (e.g. 301-2A>G)
    • -N+M / -N-M = nucleotide in an intron in the 5'UTR (e.g. -45+4A>G)
    • *N+M / *N-M = nucleotide in an intron in the 3'UTR (e.g. *212-2A>G)
    • NOTE: suggestions have been made to specifically number non-transcribed nucleotides (i.e. 5' of the transcription initiation site (cap-site) or 3' of the polyA-addition site), but these are currently not part of the HGVS recommendations (see Discussion).
      
• specific characters
  • + (plus) = see Standards - numbering
  • - (minus) = see Standards - numbering
  • * (asterisk) = translation termination (stop) codon (see Standards - amino acids)
  • _ (underscore) = nucleotide numbering, used to indicate a range (e.g. in combination
            with a deletion, duplication, insertion or variable sequence)
  • > (greater then) = changes to (substitution)
    • c.5T>G substitution
      NOTE: used at DNA and RNA level, not at protein level
  • : (colon) = separates the description of a reference sequence and the actual description of a variant 
            e.g. M13855.3:c.1A>G
  • [] = encloses changes from one allele (chromosome)
    • c.[76A>C; 83G>C] two changes in one allele (chromosome)
    • c.[76A>C];[83G>C] changes in the two alleles (chromosomes)
    • c.123+74TG[4];[5] a TG di-nucleotide repeat of length 4 on one allele and of length 5 on the other allele
    • c.32-?_357+?[3]  a triplication of an exon (coding DNA reference sequence running from nucleotide 32 to 357)
  • ; (semi-colon) =  separator between different changes in one allele or between two alleles
    • c.[76A>C]; [83G>C] changes in the two alleles (chromosomes)
    • c.[76A>C; 83G>C] two changes in one allele (chromosome)
    • c.[76A>C (;) 83G>C] two changes where it is unknown whether they are in the same or different alleles (chromosomes)
  • ^ = or
    • c.[370A>C^372C>R] back translation of the variant p.Ser124Arg, where the Ser-124 codon at c.370_372 is AGC; assuming a substitution change Arg-124 can be encoded by six possible codons, CGN (CGA, CGG, CGC, CGT) and AGR (AGA, AGG)
  • , (comma) =  separator between different transcripts or proteins generated from one allele (chromosome)
    • r.[76a>c, 73_87del] denotes the nucleotide change c.76A>C causing the appearance of two RNA molecules, one carrying variant 76a>c, and one containing a deletion of nucleotides 73 to 87
    • p.[Asn26His, Ala25_Gly29del] denotes two protein changes deriving from a change in one allele at DNA level (c.76A>C) resulting in two transcripts (r.[76a>c, 73_88del] ); amino acid Asparagine-25 to Histidine and a deletion of amino acids Asparagine-25 to Glycine-29
    •  
  • =  (equals) = indicates 'identical to reference sequence' (no change, wild type sequence)
  • ? (question mark) = unknown
  • / = mosaic cases; separator between the different nucleotides, transcripts and proteins generated from one allele (chromosome, like used by the ISCN)
    • c.[=/85C>T] somatic or germline mosaicism, i.e. the sample is a mix of c.= and c.85C>T alleles
  • // = chimeric cases, separator between different nucleotides, transcripts and proteins generated from a mix of four alleles (chromosomes, like used by the ISCN)
    • c.[=//85C>T] chimerism, i.e. the sample is a mix of two different populations of genetically distinct cells
  • ( ) = indicates uncertainty in the description of a change
    • c.[76A>C (;) 83G>C] two changes where it is unknown whether they are in the same or different alleles (chromosomes)
    • c.123+74TG(3_6) a TG di-nucleotide repeat found repeated 3 to 6 times in the population (located at nucleotide 74 in the intron following coding DNA nucleotide c.123)
  • 0 (zero) = indicates no product / nothing
    • c.0 = no DNA from allele detected, e.g. c.[76A>C];[0] for a variant in a X-linked gene in a male
    • r.0 = no RNA from allele detected, e.g. from a promoter variant or deletion
    • p.0 = no protein from allele detected, e.g. from a variant in the translation initiation codon
  • Under discussion
    { } (curly braces) = enclose "sub-alleles", i.e. changes within the range of duplications, inversions, insertions and gene conversions using nested and composite change formats (see Proposal for complex variants)
    •  c.24_65dup{46G>T} an duplication of nucleotides 24 to 65 with a the variant c.46G>T in the duplicated copy
      
• nucleotides, codons & amino acids (V2.0)
  • DNA
  • RNA
  • protein
    • one and three letter amino acid code
    • * = translation termination codon  (stop codon)
      
• others
  • chr = chromosome (e.g. chr19 or chrX)
  • del = deletion
  • dup = duplication
  • ext = extension (e.g. N- or C-terminus of protein)
  • ins = insertion
  • inv = inversion
  • con = (gene) conversion
  • fs = frame shift
  • t = translocation; e.g. t(X;4)(p21.2;q34)

Nucleotides (DNA / RNA)

For the complete and official list with further details go to IUPAC-IUBMB or NCBI site.

RNA

Genetic code

One letter code	Three letter code	Amino acid	Possible codons	Systemic name	Formula
A	Ala	Alanine	GCA, GCC, GCG, GCT	2-Aminopropanoic acid	CH3-CH(NH2)-COOH
B	Asx	Aspartic acid or Asparagine	AAC, AAT, GAC, GAT
C	Cys	Cysteine	TGC, TGT	2-Amino-3-mercaptopropanoic acid	HS-CH2-CH(NH2)-COOH
D	Asp	Aspartic acid	GAC, GAT	2-Aminobutanedioic acid	HOOC-CH2-CH(NH2)-COOH
E	Glu	Glutamic acid	GAA, GAG	2-Aminopentanedioic acid	HOOC-[CH2]2-CH(NH2)-COOH
F	Phe	Phenylalanine	TTC, TTT	2-Amino-3-phenylpropanoic acid	C6H5-CH2-CH(NH2)-COOH
G	Gly	Glycine	GGA, GGC, GGG, GGT	Aminoethanoic acid	CH2(NH2)-COOH
H	His	Histidine	CAC, CAT	2-Amino-3-(1H-imidazol-4-yl)-propanoic acid
I	Ile	Isoleucine	ATA, ATC, ATT	2-Amino-3-methylpentanoic acid	C2H5-CH(CH3)-CH(NH2)-COOH
K	Lys	Lysine	AAA, AAG	2,6-Diaminohexanoic acid	H2N-[CH2]4-CH(NH2)-COOH
L	Leu	Leucine	CTA, CTC, CTG, CTT, TTA, TTG	2-Amino-4-methylpentanoic acid	(CH3)2CH-CH2-CH(NH2)-COOH
M	Met	Methionine	ATG (translation initiation)	2-Amino-4-(methylthio)butanoic acid	CH3-S-[CH2]2-CH(NH2)-COOH
N	Asn	Asparagine	AAC, AAT	2-Amino-3-carbamoylpropanoic acid	H2N-CO-CH2-CH(NH2)-COOH
P	Pro	Proline	CCA, CCC, CCG, CCT	Pyrrolidine-2-carboxylic acid
Q	Gln	Glutamine	CAA, CAG	2-Amino-4-carbamoylbutanoic acid	H2N-CO-[CH2]2-CH(NH2)-COOH
R	Arg	Arginine	AGA, AGG, CGA, CGC, CGG, CGT	2-Amino-5-guanidinopentanoic acid	H2N-C(=NH)-NH-[CH2]3-CH(NH2)-COOH
S	Ser	Serine	AGC, AGT, TCA, TCC, TCG, TCT	2-Amino-3-hydroxypropanoic acid	HO-CH2-CH(NH2)-COOH
T	Thr	Threonine	ACA, ACC, ACG, ACT	2-Amino-3-hydroxybutanoic acid	CH3-CH(OH)-CH(NH2)-COOH
U	Sec	Selenocysteine	TGA, ...		H2N-CH(COOH)--CH2-SeH
V	Val	Valine	GTA, GTC, GTG, GTT	2-Amino-3-methylbutanoic acid	(CH3)2CH-CH(NH2)-COOH
W	Trp	Tryptophan	TGG	2-Amino-3-(lH-indol-3-yl)-propanoic acid
X	Xaa	unknown or  'other'	NNN
Y	Tyr	Tyrosine	TAC, TAT	2-Amino-3-(4-hydroxyphenyl)-propanoic acid
Z	Glx	Glutamic acid or Glutamine
*	*  (Ter)	Termination	TAA, TAG, TGA (translation termination)	HGVS addition (V2.0)
Used in alignments only
-	-	gap of indeterminate length			-

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