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" |
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Examples |
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Explanation of Symbols | |
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Notes#
coordinate_type
may be g, m, c, or n (genomic, mitochondrial, coding DNA and non-coding DNA).position(s)_deleted
should contain two different positions, e.g.123_126
not123_123
.- the
position(s)_deleted
should be listed from 5' to 3', e.g.123_126
not126_123
.- exception: when a circular genomic reference sequnce 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
..GAT gta..//..cag TCA..
changes to..GA_ gta..//..cag TCA..
, based on a coding DNA reference sequence the variant is described asLRG_199t1:c.3921del
(NC_000023.10:g.32459297del
) and not asc.3922del
(which would translate tog.32456507del
)
- exception: deletions around exon/exon junctions when identical nucleotides flank the junction (see Numbering); : when
- † = see Uncertain; when the postion 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 T at positiong.33344591
in the sequence TGTGA
TTCT to TGTG_
TTCT: NOTE: the recommendation is not to describe the variant asNC_000023.11:g.33344591delT
, 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 positionc.5697
in the sequence ATTGAAAAAAAA
TTAG to ATTGAAAA_AAA
TTAG, i.e. the last A of the 8 nucleotide A-stretch running from positionc.5690
toc.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 positiong.32343183
in the sequence CTAATTTTTTTT
CAAT to CTAATTTT_TTT
CAAT, i.e. the last T of the 8 nucleotide T-stretch running from positiong.32343176
tog.32343183
- NOTE: the T nucleotide in
NC_000023.11:g.32343183
corresponds to the A nucleotide inNM_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 asNM_004006.2:c.5697del
(not asNM_004006.2:c.5690del
).
- NOTE: the T nucleotide in
-
several nucleotides
NC_000023.11:g.33344590_33344592del
: a deletion of nucleotidesg.33344590
tog.33344592
in the sequence GTGTGAT
TCTG to GTGT___
TCTG: NOTE: the recommendation is not to describe the variant asNC_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 nucleotidesc.183
toc.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 ..GAT
gta..//..cag TCA.. changing to ..GA_
gta..//..cag TCA..
NOTE : according to an exception of the 3'rule the variant (NC_000023.10:g.32459297del
) is not described asc.3922del
since this would shift the position of the variant to the next exon (c.3922
linking tog.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 sequenceGAACAG
changing tog
t.../..agTGCCTTGAACAG
(not_
t.../..agTGCCTTc.1704del
)
NOTE: this description does not depend on the effect observed on RNA level, giving either altered splicing orr.1704del
- intron/exon
LRG_199t1:c.1813del
: the deletion of the G nucleotide at the intron/exon border in the sequenceCTGGCCgt.../..ag
changing toG
TTTTACTGGCCgt.../..ag
(not_
TTTTAc.1813-1del
)
NOTE: this description does not depend on the effect observed on RNA level, giving either altered splicing orr.1813del
- exon/exon
-
exons
NC_000023.11(NM_004006.2):c.4072-1234_5155-246del
: a deletion of nucleotidesc.4072-1234
toc.5155-246
removing exon 30 (starting at positionc.4072
) to exon 36 (ending at positionc.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 positionc.4072
) to exon 36 (ending at positionc.5154
) of the DMD-gene. The deletion break point has not been sequenced. Exons 29 (ending atc.4071
) and 37 (starting at nucleotidec.5155
) have been tested and shown to be not deleted. The deletion therefore starts in intron 29 (positionc.4071+1
toc.4072-1
) and ends in intron 36 (positionc.5154+1
toc.5155-1
).
NOTE : previously, the suggestion was made to describe such deletions using the formatNC_000023.11(NM_004006.2):c.4072-?_5154+?del
. However, sincec.4072-?
indicates an unknown postion 5' ofc.4072
andc.5154+?
to an unknown postion 3' ofc.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 testedc.4196
) to exon 36 (deleted position testedc.5090
) of the DMD-gene. The deletion break point has not been sequenced. Exons 29 (position testedc.3996
) and 37 (position testedc.5284
) are not deleted.
- general, "exon-based" description:
- 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 likeNC_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 positionsg.31120496
andg.33339477
are defined by the first nucleotide of the probe 3' of the ligation site for the resp. the last and first exons tested.
NC_000023.11:g.33344590_33344592=/del
: a mosaic case where from positiong.33344590
tog.33344592
besides the normal sequence also chromosomes are found containing a deletion of this sequenceNC_000023.11:g.33344590_33344592=//del
: a chimeric case, i.e. the sample is a mix of cells containingg.33344590_33344592=
andg.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 Recommendations General), 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 realy 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 ..-ATC-TTT-GGT-.. (c.1519
to c.1527
). Three different deletions (TC-T, C-TT and -TTT-) would give the reported protein variant "Phe508del". Applying the 3' rule see Recommendations yields two different changes at DNA level, NM_000492.3:c.1521_1523del
and NM_000492.3:c.1522_1524del
. When you assume the change at DNA level is c.1522_1524delTTT
, deletion of exactly the Phe508 encoding triplet, you are wrong. The change found in patients is mostly NM_000492.3:c.1521_1523delCTT
. So, without a proper description in the manuscript one can not be certain.
Suggest to use "los" for a loss from a mononucleotide 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 (JdD): 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.