ASXL1 c.3926dup, p.Asn1309LysfsTer20
NM_015338.5:c.3926dup
Pathogenic
The ASXL1 c.3926dupA variant causes a frameshift and premature stop leading to loss of function in a gene where LoF is a known disease mechanism, is absent from population databases, and is supported by well-established functional studies demonstrating a damaging effect; thus classified as Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.3926dup
Protein Change
N1309Kfs*20
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 1309 in gene ASXL1
Variant interpretation based on transcript NM_015338.6
Genome Browser
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HGVS InputNM_015338:c.3926dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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 1309 in gene ASXL1
Functional Summary
The ASXL1 N1309Kfs*20 variant is a truncating mutation that likely results in loss of function of the ASXL1 protein, a tumor suppressor and epigenetic regulator. Functional studies have shown that ASXL1 truncating mutations can lead to the production of C-terminally truncated proteins, often resulting in the loss of the PHD domain. These mutations have been associated with dedifferentiation and myelodysplastic syndrome in murine models, supporting a damaging effect in the context of myeloid malignancies.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: c.3926dupA (N1309Kfs*20) is a frameshift duplication predicted to create a premature stop codon and cause loss of function in ASXL1, where LoF is an established disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null frameshift expected to abolish normal protein function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no known variant results in the same amino acid change (N1309Kfs*20) by a different nucleotide alteration. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: there is no information regarding de novo occurrence with confirmed parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: functional studies in murine models demonstrate that ASXL1 truncating mutations produce C-terminally truncated proteins lacking the PHD domain, leading to dedifferentiation and myelodysplastic syndrome, supporting a damaging effect. Therefore, this criterion is applied at Strong strength because multiple well-established experiments show functional damage.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data demonstrating a statistically significant enrichment in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: c.3926dupA does not reside in a recognized hot spot or specific functional domain beyond general truncation. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive) in population databases". The evidence for this variant shows: the variant is absent from gnomAD and other large population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because it is not observed in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on biallelic occurrence or recessive inheritance. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a frameshift leading to truncation, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no reports of assumed de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: in silico splicing predictors yield a SpliceAI max score of 0.01, indicating minimal impact; no missense impact is relevant. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – Patient’s phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no specific phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: it is not found in ClinVar or similar databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder". The evidence for this variant shows: allele frequency is zero, not high. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is zero, not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – Lack of segregation in affected family members". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: it is a loss-of-function frameshift, not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a frameshift, not an in-frame change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational evidence addresses splicing only and indicates minimal effect, but the variant’s pathogenic mechanism is truncation. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no such benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a frameshift, not synonymous. Therefore, this criterion is not applied.