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Deletion#

Deletion: a sequence change where, compared to a reference sequence, one or more nucleotides are not present (deleted).

Syntax#

Syntax sequence_identifier ":" coordinate_type "." position_or_range "del"
  • position_or_range may be a single position or a range
Examples
  • NC_000001.11:g.1234del
  • NC_000001.11:g.1234_2345del
Explanation of Symbols
  • coordinate_type: The type of molecule and coordinate system; see the general recommendations.
  • position_or_range: The position OR range
  • sequence_identifier: an identifier for a sequence from a recognized database
See also explanation of grammar used in HGVS Nomenclature.

Notes#

  • position(s)_deleted should contain two different positions, e.g., 123_126, not 123_123.
  • the position(s)_deleted should be listed from 5' to 3', e.g., 123_126, not 126_123.
    • exception: when a circular genomic reference sequence is used ("o" and "m" prefix) nucleotide positions may be listed from 3' to 5' when the deletion includes both the last and first nucleotides of the reference sequence.
  • 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".
      NOTE: the SVD-WG has prepared a proposal to modify this recommendation (see SVD-WG010). The new proposal is: two variants that are separated by two or fewer intervening nucleotides (that is, not including the variants themselves) should be described as a single "delins" variant.
  • for all descriptions, the most 3' position possible of the reference sequence is arbitrarily assigned to have been changed (3'rule).
    • exception: deletions around exon/exon junctions when identical nucleotides flank the junction (see Numbering);
      when ..GATgta..//..cagTCA.. changes to ..GAgta..//..cagTCA.., based on a coding DNA reference sequence, the variant is described as LRG_199t1:c.3921del (NC_000023.10:g.32459297del) and not as c.3922del (which would translate to g.32456507del).
  • † = see Uncertain; when the position and/or the sequence of a deletion has not been defined, a description may have a format like g.(100_150)del(15).

Examples#

  • one nucleotide

    • NC_000023.11:g.33344591del
      a deletion of the A at position g.33344591 in the sequence TGTGATTCT to TGTGTTCT.
      NOTE: the recommendation is not to describe the variant as NC_000023.11:g.33344591delA, i.e., describe the deleted nucleotide sequence. This description is longer, it contains redundant information, and chances to make an error increases (e.g., NC_000023.11:g.33344591delG).

    • NM_004006.2:c.5697del (3'rule)
      a deletion of the A at position c.5697 in the sequence ATTGAAAAAAAATTAG to ATTGAAAAAAA.TTAG, i.e., the last A of the 8 nucleotide A-stretch running from position c.5690 to c.5697.
      NOTE: the 3'rule has been applied here stating that "for all descriptions, the most 3' position possible is arbitrarily assigned to have been changed" (see General_Recommendations).

    • NC_000023.11:g.32343183del (3'rule)
      a deletion of the T at position g.32343183 in the sequence CTAATTTTTTTTCAAT to CTAATTTTTTT.CAAT, i.e., the last T of the 8 nucleotide T-stretch running from position g.32343176 to g.32343183. NOTE: the T nucleotide in NC_000023.11:g.32343183 corresponds to the A nucleotide in NM_004006.2:c.5690, a transcript annotated on the minus strand of the X-chromosome. However, applying the 3'rule, the deletion of this nucleotide based on a coding DNA reference sequence (transcript level) should be described as NM_004006.2:c.5697del (not as NM_004006.2:c.5690del).

  • several nucleotides

    • NC_000023.11:g.33344590_33344592del
      a deletion of nucleotides g.33344590 to g.33344592 in the sequence GTGTGATTCTG to GTGT.TCTG.
      NOTE: the recommendation is not to describe the variant as NC_000023.11:g.33344590_33344592delGAT, i.e., describe the deleted nucleotide sequence. This description is longer, it contains redundant information, and chances to make an error increases (e.g., NC_000023.11:g.33344590_33344592delTTA).

    • NC_000023.11(NM_004006.2):c.183_186+48del
      a deletion of nucleotides c.183 to c.186+48 (coding DNA reference sequence), crossing an exon/intron border.

  • exon/intron/exon

    • exon/exon

      • LRG_199t1:c.3921del
        the deletion of the T nucleotide at the exon/exon border in the sequence ..GATgta..//..cagTCA.. changing to ..GAgta..//..cagTCA...
        NOTE: according to an exception to the 3'rule, the variant (NC_000023.10:g.32459297del) is not described as c.3922del since this would shift the position of the variant to the next exon (c.3922 linking to g.32456507) (see exception in Numbering and see Q&A).

    • exon/intron

      • LRG_199t1:c.1704+1del
        the deletion of the G nucleotide at the exon/intron border in the sequence GAACAGgt..//..agTGCCTT changing to GAACAGt..//..agTGCCTT (not c.1704del).
        NOTE: this description does not depend on the effect observed on RNA level, giving either altered splicing or r.1704del.

    • intron/exon

      • LRG_199t1:c.1813del
        the deletion of the G nucleotide at the intron/exon border in the sequence CTGGCCgt..//..agGTTTTA changing to CTGGCCgt..//..agTTTTA (not c.1813-1del).
        NOTE: this description does not depend on the effect observed on RNA level, giving either altered splicing or r.1813del.

  • exons

    • NC_000023.11(NM_004006.2):c.4072-1234_5155-246del
      a deletion of nucleotides c.4072-1234 to c.5155-246 removing exon 30 (starting at position c.4072) to exon 36 (ending at position c.5154) of the DMD gene.
      NOTE: c.4072-1234_5155-246delXXXXX, the size of the deletion (XXXXX) should not be described.

    • break point not sequenced
      recommended is to describe the deletion detected as precise as possible, see Uncertain for examples. In practice, most people use the so-called "exon-based description", a general description which does not contain specific information regarding the exact nucleotide positions tested.

      • general, "exon-based" description
        NC_000023.11(NM_004006.2):c.(4071+1_4072-1)_(5154+1_5155-1)del
        a deletion of exon 30 (starting at position c.4072) to exon 36 (ending at position c.5154) of the DMD gene. The deletion break point has not been sequenced. Exons 29 (ending at c.4071) and 37 (starting at nucleotide c.5155) have been tested and shown to be not deleted. The deletion therefore starts in intron 29 (positions c.4071+1 to c.4072-1) and ends in intron 36 (positions c.5154+1 to c.5155-1).
        NOTE: previously, the suggestion was made to describe such deletions using the format NC_000023.11(NM_004006.2):c.4072-?_5154+?del. However, since c.4072-? indicates an unknown position 5' of c.4072 and c.5154+? to an unknown position 3' of c.5154 this description is not correct when it is known that exons 29 and 37 are present. See also SVD-WG003 (undecided).

      • specific description
        NC_000023.11(NM_004006.2):c.(3996_4196)_(5090_5284)del
        probe-based description of a deletion, identified by MLPA, of exon 30 (deleted position tested c.4196) to exon 36 (deleted position tested c.5090) of the DMD gene. The deletion break point has not been sequenced. Exons 29 (position tested c.3996) and 37 (position tested c.5284) are not deleted.

    • deletions extending beyond the transcribed region
      following current recommendations (see Numbering), it is not allowed to describe variants in nucleotides beyond the boundaries of a reference sequence. Consequently, deletions extending 5' of a transcript can not be described like NC_000023.11(NM_004006.2):c.(?_-244)_(31+1_32-1)del (c.-244 is the first nucleotide of NM_004006.2). Deletions extending 3' of a transcript can not be described like NC_000023.11(NM_004006.2):c.(10086+1_10087-1)_(*2691_?)del (c.*2691 is the last nucleotide of NM_004006.2). Such deletions can only be described using genomic coordinates. The HGVS nomenclature committee (SVD-WG) is discussing whether a c. based format should be proposed.

  • gene

    • NC_000023.11:g.(31060227_31100351)_(33274278_33417151)del
      a deletion of the entire DMD gene based on a SNP-array analysis where the maximum size of the deletion lies between SNPs rs396303 and rs7887548 (nucleotides 31060227 and 33417151) and the minimum size between SNPs rs808178 and rs7887103 (nucleotides 31100351 and 33274278).

    • NC_000023.11:g.(?_31120496)_(33339477_?)del
      a deletion of the entire DMD gene based on a MLPA assay where the nucleotide positions g.31120496 and g.33339477 are defined by the first nucleotide of the probe 3' of the ligation site for, respectively, the last and first exons tested.

  • other

    • NC_000023.11:g.33344590_33344592=/del
      a mosaic case where from position g.33344590 to g.33344592, besides the normal sequence, also chromosomes are found containing a deletion of this sequence.

    • NC_000023.11:g.33344590_33344592=//del
      a chimeric case, i.e. the sample is a mix of cells containing g.33344590_33344592= and g.33344590_33344592del.

Discussion#

Can I use NG_012232.1:g.123del6 to describe a 6 nucleotide deletion?

No, a deletion of more than one residue should mention the first and last residue deleted, separated using the range symbol ("_", underscore), e.g., NG_012232.1:g.123_128del and not NG_012232.1:g.123del6.

In the example above, LRG_199t1:c.3921del, should the description based on a coding DNA reference sequence not be LRG_199t1:c.3922del?

Strictly speaking, you are right. However, for cases like this an exception was made to prevent that when c.3922del is translated back to a genomic position one would end up at the wrong nucleotide in the wrong exon (NC_000023.10:g.32456507del instead of NC_000023.10:g.32459297del).

Is the description of a deletion of exon 17 as c.EX17del still allowed?

A description like c.EX17del has never been allowed. Descriptions should be specific and indicate the nucleotides affected by the change.

Deletions in the BRCA1 gene are usually mediated by Alu sequences having a very high homology, reaching 100% in the breakpoint region. In such cases, what nucleotide should be used to describe the deletion breakpoint?

In cases like this, the 3'rule applies (see General Recommendations), i.e., the deletion breakpoint is determined by the first nucleotide that differs after shifting the alignment as far 3' as possible. The first nucleotide differing is the first nucleotide deleted.

PCR analysis of a gene on the X-chromosome shows products for exons 1_3, no product is detected for exons 4_14 (exon 14 is the last exon of the gene). Since PCR fails already when one primer is not hybridising, we are not sure whether exon 4 and 14 are completely absent, or only partially. To describe the deletion I would therefore like to use the last base of exon 3 with "+?" and the last base of exon 13 with a "+?". What are your recommendations? (Erik-Jan Kamsteeg, Nijmegen, Nederland)

Literally speaking, you are right and it is best to set the borders as precise as possible. When exon 3 is present, the location of the reverse primer can be used to set the most 5' border (something like c.987+123). However, for the 3' end, your reasoning does not make a difference. Since you do not know how far the deletion extends, you have no positive PCR limiting the deletion at the 3' end, using the location of exon 13 since exon 14 might be present would give the wrong impression. Consequently, the precise description can only be like c.(987+123_?)del. Is this really more informative then c.(987+1_?)del, using the exon 3 exon/intron border?

In literature I often see the description "deltaF508" for a variant in the CFTR gene in patients with Cystic Fibrosis. Is the variant detected in these patients NM_000492.3:c.1522_1524delTTT?

No. The sequence surrounding amino acid Phe508 in the CFTR gene is ..ATCTTTGGT.. (c.1519 to c.1527). Three different deletions (..ATCTTTGGT.., ..ATCTTTGGT.., and ..ATCTTTGGT..) would give the reported protein variant p.Phe508del. Applying the 3' rule (see Recommendations) yields two different changes on DNA level, NM_000492.3:c.1521_1523del and NM_000492.3:c.1522_1524del. When you assume the change on DNA level is c.1522_1524del, deletion of exactly the Phe508 encoding triplet, you are wrong. The change found in patients is mostly NM_000492.3:c.1521_1523del. So, without a proper description in the manuscript, one can not be certain.

Suggestion to use "los" for a loss from a mono-nucleotide stretch.

Pat O'Neill (Burlington, USA) writes: I especially like the use of "dup" in place of "ins" when the insertion creates a run of two or more nucleotides. I feel that there should be a parallel term for the loss of a nucleotide from a run of two or more instead of just "del". This is because of the mechanistic implications of both an ins and a del of a nucleotide in a run. Has this been discussed? My thought for a term in place of "del" is "los" for loss.

Shuji Ogino (Boston, USA) agrees, but suggests to use "dec" for a decrease in length.

Reply (Johan den Dunnen, Netherlands): The "dup" nomenclature was introduced because it is simpler, shorter and less confusing (see above). The potential mechanistic relation is nice but was not decisive. Basically, a description should be clear/unequivocal and it is not intended to contain other information.