ASXL1 c.1934dupG, p.Gly646TrpfsTer12
NM_015338.5:c.1934dupG
COSMIC ID: COSM1411076
Pathogenic
Final classification of NM_015338.5:c.1934dupG in gene ASXL1 is Pathogenic. This classification is supported by strong evidence of a null variant (PVS1), functional studies indicating a damaging effect (PS3), very low population frequency (PM2), and multiple reputable sources reporting the variant as pathogenic (PP5).
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
ASXL1
Transcript
NM_015338.6
MANE Select
Total Exons
13
Strand
Forward (+)
Reference Sequence
NC_000020.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_015338.5 | RefSeq Select | 13 exons | Forward |
| NM_015338.4 | Alternative | 13 exons | Forward |
| NM_015338.3 | Alternative | 13 exons | Forward |
Variant Details
HGVS Notation
NM_015338.5:c.1934dupG
Protein Change
G646Wfs*12
Location
Exon 13
(Exon 13 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 646 in gene ASXL1
Alternate Identifiers
COSM1411076
Variant interpretation based on transcript NM_015338.6
Genome Browser
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HGVS InputNM_015338:c.1934dupG
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0495%
Low Frequency
Highest in Population
Remaining individuals
0.0767%
Common
Global: 0.0495%
Remaining individuals: 0.0767%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 244252Alt: 121Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is common in the population (0.049500% MAF).
Classification
2 publications
Likely Pathogenic
Based on 13 submitter reviews in ClinVar
Submitter Breakdown
11 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Variant summary: ASXL1 c.1934dupG (p.Gly646TrpfsX12) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in association with Bohring-Opitz syndrome in the HGMD/LOVD databases. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1934dupG has been reported in the literature as a de-novo variant in at-least two individuals affected with Bohring-Opitz Syndrome (example, Kibe_2017, Urreizti_2018). As this variant is located in a homopolymer tract of guanines it is prone to replication slippage and could be overrepresented as sequencing artifacts. This variant has also been reported to be a common cancer-associated ASXL1 variant in settings of myeloid malignancies (Van Ness_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 426927). Based on the evidence outlined above, in settings where somatic mosaicism, clonal hematopoiesis of indeterminate potential (CHIP) and technical artifacts of analysis are ruled out, the variant was classified as pathogenic in association with Bohring-Opitz Syndrome.
This sequence change creates a premature translational stop signal (p.Gly646Trpfs*12) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 896 amino acid(s) of the ASXL1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Bohring-Opitz syndrome (PMID: 29681105, 30147881). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426927). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Likely pathogenic (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 646 in gene ASXL1
Functional Summary
The ASXL1 G646Wfs*12 variant is functionally characterized as likely oncogenic. It is located in the SRC1-binding domain of the ASXL1 protein and has been associated with primary myelofibrosis. Functional studies in murine models demonstrate that ASXL1 truncation mutations lead to dedifferentiation and myelodysplastic syndrome, supporting a damaging effect. Additionally, this variant is linked to worse survival outcomes in patients with primary myelofibrosis. There is no mention of other pathogenic variants at the same position or codon.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: NM_015338.5:c.1934dupG is a truncating variant in ASXL1, where loss of function is associated with disease. Therefore, this criterion meets the requirements because it is a null variant in a gene where LoF is a known mechanism of disease.
PS3
PS3 (Strong)
According to VCEP guidelines: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: Functional studies indicate that the ASXL1 G646Wfs*12 variant is likely oncogenic and associated with primary myelofibrosis, demonstrating a damaging effect. Therefore, this criterion meets the requirements because there are well-established functional studies supporting a damaging effect.
PM2
PM2 (Moderate)
According to VCEP guidelines: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: The variant has a minor allele frequency of 0.0495% in gnomAD, indicating it is extremely rare. Therefore, this criterion meets the requirements because the variant is absent from controls at an extremely low frequency.
PP5
PP5 (Supporting)
According to VCEP guidelines: 'Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: The variant has been reported as Pathogenic by 11 clinical laboratories in ClinVar. Therefore, this criterion meets the requirements because there is a reputable source reporting the variant as pathogenic.