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Alleles#

Allele: a series of variants on one chromosome.

Syntax#

Variants in cis
Syntax sequence_identifier ":" coordinate_type ".[" position_edit ";" position_edit "]"
Examples
  • NC_000001.11:g.[123G>A;345del]
Variants in trans
Syntax sequence_identifier ":" coordinate_type ".[" position_edit "];[" position_edit "]"
Examples
  • NC_000001.11:g.[123G>A];[345del]
Variants with unknown or uncertain phase
Syntax sequence_identifier ":" coordinate_type "." position_edit "(;)" position_edit
Examples
  • NC_000001.11:g.123G>A(;)345del
Explanation of Symbols
  • coordinate_type: The type of molecule and coordinate system; see the general recommendations.
  • position_edit: A string that concatenates a position and edit, such as 2376=, 2376_2399dup, or 2376_2377insGT.
  • sequence_identifier: an identifier for a sequence from a recognized database
See also explanation of grammar used in HGVS Nomenclature.

Notes#

  • humans are diploid organisms and have two alleles at each genetic locus, with one allele inherited from each parent.
  • when two variants are identified in a gene that are on one chromosome (in cis), this should be described as g.[variant1;variant2].
  • when two variants are identified in a gene that are on different chromosomes (in trans), this should be described as g.[variant1];[variant2].
  • using allele descriptions involving two or more different variants: you do not indicate the other allele does not contain the variant (unless one allele contains no variants at all). LRG_199t1:c.[2376G>C];[3103del] is correct, LRG_199t1:c.[2376G>C;3103=];[2376=;3103del] is not correct.
  • when two variants are identified in a gene, but when it is not known whether these are on one chromosome (in cis) or on different chromosomes (in trans), this should be described as variant1(;)variant2, i.e. without using [ ].
    NOTE: in the latest publication of the recommendations (Den Dunnen et al. (2016)), the example given is not correct.
    NOTE: it is recommended to determine whether the changes are on the same chromosome or not.
  • descriptions combining variants based on different reference sequence types (e.g., c.[76A>C];g.[10091C>G]) should not be used.

Examples#

Variants in cis#

  • NM_004006.2:c.[2376G>C;3103del]
    one allele (chromosome) of a gene contains two different changes, c.2376G>C and c.3103del. The variants are found in cis.

  • NC_000023.10:g.[30683643A>G;33038273T>G]
    one allele (X-chromosome) contains two different variants in two different genes, g.30683643A>G in the GK gene and g.33038273T>G in the DMD gene.

  • NC_000003.12:g.63912687AGC[(50_60)]
    one allele (chromosome 3) contains a repeated AGC tri-nucleotide sequence, starting at position g.6391268, containing 50 to 60 AGC copies.

  • NC_000003.12:g.63912687AGC[(60_?)]
    one allele (chromosome 3) contains a repeated AGC tri-nucleotide sequence, starting at position g.6391268, containing 60 or more AGC copies.

Variants in trans#

  • NM_004006.2:c.[2376G>C];[3103del]
    the two alleles (chromosomes) of a gene each contain a different change, c.2376G>C and c.3103del. The variants are found in trans. A heterozygous case (compound heterozygote, e.g., in a recessive disease).
    NOTE: do not use c.[2376G>C;3103=];[2376=;3103del], the indication "not changed" is used only when one variant was identified (like LRG_199t1:c.[2376G>C];[2376=]).

  • NM_004006.2:c.[2376G>C];[2376G>C]
    both alleles (chromosomes) of a gene contain the same variant, c.2376G>C. A homozygous case (e.g., in a recessive disease).
    NOTE: it is not allowed to shorten this to c.2376[G>C];[G>C] or even c.2376G>C[];[].

  • NM_004006.2:c.[296T>G;476T>C;1083A>C];[296T>G;1083A>C]
    a sample contains variants c.296T>G and c.1083A>C on both alleles (chromosomes) and variant c.476C>T on only one allele.

  • NM_004006.2:c.[2376G>C];[2376=]
    one allele (chromosome) of a gene contains a variant, c.2376G>C, the other allele (chromosome) contains the reference sequence, c.2376= (is wild-type).
    NOTE: the description c.[2376G>C];[=], containing c.2376G>C and c.=, is different since it indicates the entire coding DNA reference sequence was analysed and the only variant identified was c.2376G>C (on one allele). NOTE: for other variant types, the format is c.[2376del];[2376=], c.[2376_2399dup];[2376_2399=], c.[2376_2377insGT];[2376_2377=], etc. For more examples, see Proposal SVD-WG001.

  • NM_004006.2:c.[2376G>C];[?]
    one allele (chromosome) of a gene contains a variant, c.2376G>C, while a variant for the other allele is expected but not yet identified (c.?) (e.g., in individuals affected by a recessive disease).

Variants with unknown or uncertain phase#

  • NM_004006.2:c.2376G>C(;)3103del
    two variants in a gene, c.2376G>C and c.3103del, but it is not known whether they are on the same or on different alleles (chromosomes).
    NOTE: in the latest publication of the recommendations (Den Dunnen et al. (2016)), the example given is not correct. Allele brackets should not be used when it is not known whether variants are on one allele or not.

  • NM_004006.2:c.2376G>C(;)(2376G>C)
    analysis detects one variant (c.2376G>C), suggesting both alleles (chromosomes) contain this variant, but it can not be excluded the other allele is deleted.

  • NM_004006.2:c.[296T>G;476T>C];[476T>C](;)1083A>C
    a sample contains a homozygous variant (c.476T>C) and two heterozygous variants (c.296T>G and c.1083G>C) for which it is not known on which allele (chromosome) they are (although at least one, in the example c.296T>G, is on the same allele as c.476T>C).

  • NM_004006.2:c.[296T>G];[476T>C](;)1083G>C(;)1406del
    a sample contains heterozygous variants on different alleles (c.296T>G and c.476T>C) and two additional heterozygous variants (c.1083G>C and c.1406del) for which it is not known on which allele (chromosome) they are.

Discussion#

Was originally the recommendation to use the format [c.76A>C+c.83G>C]?

Indeed, originally den Dunnen and Antonarakis, 2000 the suggestion was to describe two changes in a gene on one chromosome as [c.76>C+c.83G>C], i.e. using a "+"-character to separate the two changes, while an earlier publication suggested to use a ";" ([c.76A>C;c.83G>C] (Antonarakis and the Nomenclature Working Group, 1998). To prevent confusion with older publications, to improve overall consistency, and to keep descriptions as short as possible, the 2000 proposal was retracted. The recommended format is c.[76A>C;83G>C].

In recessive diseases, is it important I show in which combination variants were found?

When in one individual you find more than one variant, it is essential that you clearly indicate on which allele(s) variant(s) were found.

  • disease severity will depend on the combination of variants found;
  • in recessive disease, when two variants are on one allele, an individual is a carrier or you might not have found the variant on the second allele.

I find the notation c.[76A>C] without describing the second allele misleading; not enough researchers know this refers to only one of the two alleles present. Would using c.[76A>C];[] be OK?

No, the recommended description is LRG_199t1:c.[76A>C];[76=], i.e. c.76= for "no change" at position c.76 on the second allele.

How should I describe the variants detected in males and females for a gene on the X-chromosome?

In females, the description is straightforward, like LRG_199t1:c.[76A>C];[76=]. In males, there is no second allele (X-chromosome), which can be described as LRG_199t1:c.[76A>C];[0], i.e. using c.0 to indicate the absence of a second X-chromosome.

I have a patient with hearing loss and variants in the GJB2 (c.35delG) and GJB6 (c.689_690insT) genes in trans, how should I describe this? (Nancy Carson, Ottawa, Canada)

The recommendation is to use the format [NM_004004.2:c.35del];[NM_006783.1:c.689_690insT]. This uses standard HGVS descriptions. Another format, preventing confusion regarding which variant was found in which gene, is to describe the variants as [GJB2:c.35del];[GJB6:c.689_690insT], i.e. using the HGNC approved gene symbols. When using gene symbols, it is essential that you also define the coding DNA reference sequence used elsewhere.

When for a haplotype I have a range of changes to report, is there a suggested short format to use?

When it is once clearly specified (e.g., in the Materials & Methods) what variants are listed and based on which reference sequence(s), alleles may be reported in a simplified format like below. Variants should be listed in genomic order and using "[ ]" for variants on the same chromosome.

  • haplotype with all variants in relation to several different reference sequences, both genomic and coding DNA
    • description of the reference haplotype; [M59228.1:g.250G>C;AF209160.1:g.572CA[(11_21)];Z11861.1:g.61T>C;Z16803.1:g.114A[(18_22)]].
    • short haplotype description; [C;13;T;21].
  • haplotype with all variants in relation to one coding DNA reference sequence
    • description of the reference haplotype; NM_004006.1:c.[837G>A;1704+51T>C;3734C>T;6438+2669T[(16_23)];6571C>T;7098+13212GT[(15_19)]].
    • short haplotype description; [G;C;C;18;T;17].

Suggestion (Peter Taschner, Leiden)

Nomenclature recommendations mainly apply to genotype descriptions in tables. Unfortunately, these are not very useful in the general text of a paper. For instance, OPRM1:c.118A>G or rs1799971:A>G can be used to describe the variant, but in a paper, you might like to discuss the phenotypic consequences of different genotypes. In fact, the current recommendation is to use OPRM1:c.[118A>G];[118A=] to describe a heterozygote, and OPRM1:c.[118A=];[118A=] and OPRM1:c.[118>G];[118>G] for the homozygotes. I would like to suggest to describe the genotypes in the text like:

  • OPRM1:c.118AA homozygotes
  • OPRM1:c.118GA heterozygotes
  • OPRM1:c.118GG homozygotes

The different alleles could then be designated as the OPRM1:c.118A allele and the OPRM1:c.118G allele. In combination with variants of other genes, the genotype descriptions could be OPRM1:c.118AA, GJB2:c.76AC double heterozygotes, etc.