Community Consultation

Proposal SVD-WG010 (var distance)

• Status: open

  proposal SVD-WG010, Community Consultation closed on July 31 (2021); decision pending.

The proposal suggests to specify the HGVS nomenclature recommendations for the description of two variants which are close to each other.

• two variants that are separated by fewer than two intervening nucleotides (that is, not including the variants themselves) should be described as a single “delins” variant
  • the recommendation applies on DNA, RNA and protein level
  • HGVS requires that insertion, duplication and deletion variants are “shuffled” toward the 3’ (nucleotide) or C terminus (amino acid). However, for the purposes of evaluating adjacency, the 3’ or C-terminus shifted variant should also be shifted in the opposite direction to determine the point of closest distance. Example: the variant AGCGTTTAGC to AGGGTTTTAGC is described as g.3_4delinsGGT, not als g.[3C>G;7dup]

  • pairs of variants should be considered in order of increasing sequencing position. If variants A, B, and C occur in that order on a sequence, and A and B might be merged, and B and C might be merged, A, B and C should be merged and described as a single “delins” variant.

    NOTE: adjacent variants in cis should be described as a single “delins” variant. Data providers may report adjacent variants independently and may merge nearby (non-adjacent) variants if they believe that those forms are more suitable for their data. The intention of HGVS recommendations is to encourage a convenient convention for the most common classes of variant comparisons while not precluding other forms when appropriate.

Background

According to the current recommendations, the description of two variants which are close to each other depends on whether they are in a protein coding sequence or not.

• making a discrimination between variants in protein-coding and non-coding sequences is undesired and makes application of the recommendations unnecessarily complex.
• the proposal does ensure that tools predicting the consequences of a variant at the protein level do not make conflicting and incorrect predictions (e.g. c.235_237delinsTAT p.(Lys79Tyr) versus c.[235A>T;237G>T] (p.[(Lys79*;Lys79Asn)])

NOTE: the current recommendation is:

• two variants separated by one or more nucleotides should be described individually and not as a “delins”
• exception: two variants separated by one nucleotide, together affecting one amino acid, should be described as a “delins”

Examples

• LRG_199t1:c.235_236delinsTT

  variants c.235A>T and c.236A>T are separated by fewer than two nucleotides and described as a “delins” variant (both affect the same amino acid residue)

  NOTE: when the method used does not allow to determine whether the variants are on the same allele or not the variant should be described as LRG_199t1:c.235A>T(;)237G>T (see Alleles)

• LRG_199t1:c.235_237delinsTAT

  variants c.235A>T and c.237G>T are separated by fewer than two nucleotides and described as a “delins” variant (both affect the same amino acid residue)

• LRG_199t1:c.[235A>T;238G>T]

  variants c.235A>T and c.238G>T are separated by two nucleotides and described as separate variants, not as “delins” (c.235_238delinsTAGT)

• NC_000023.10:g.32862927_32862929delinsATA

  variants g.32862927C>A and g.32862929T>A are separated by fewer than two nucleotides and described as a “delins” variant

• LRG_199t1:c.992_1004delinsAC

  variants c.992_1002del and c.1004T>C are separated by fewer than two nucleotides and described as a “delins” variant

• NP_003997.1:p.Ser988_Gln900delinsAlaLeuHis

  variants p.Ser988 and p.Gln900 (LRG_199t1:c.[2962T>G;2970A>T]) are separated by fewer than two amino acids and described as a “delins” variant, not as p.[Ser988Ala;Gln900His]