ASXL1 c.1934del, p.Gly645ValfsTer58
NM_015338.5:c.1934del
COSMIC ID: COSM6191274
Pathogenic
NM_015338.5:c.1927del (G645Vfs*58) in ASXL1 is a truncating, loss-of-function variant with strong functional evidence and rarity in population databases, satisfying PVS1 (Very Strong), PS3 (Strong), and PM2 (Moderate), supporting a Pathogenic classification.
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.1934del
Protein Change
G645Vfs*58
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 645 in gene ASXL1
Alternate Identifiers
COSM6191274
Variant interpretation based on transcript NM_015338.6
Genome Browser
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HGVS InputNM_015338:c.1934del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0286%
Low Frequency
Highest in Population
East Asian
0.0439%
Low Frequency
Global: 0.0286%
East Asian: 0.0439%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 213340Alt: 61Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0286%, 61/213340 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0439%, 7/15956 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC ID
COSM6191274
Recurrence
63 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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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 645 in gene ASXL1
Functional Summary
The ASXL1 G645Vfs*58 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 loss of the PHD domain, contributing to oncogenic processes. In murine models, expression of ASXL1 truncating mutations has been associated with dedifferentiation and myelodysplastic syndrome, supporting a damaging effect of this variant.
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: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows: NM_015338.5:c.1927del causes a frameshift leading to G645Vfs*58, and ASXL1 loss-of-function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene where LOF causes disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change.' The evidence for this variant shows: there is no known pathogenic variant causing the same amino acid change. Therefore, PS1 is not applied because the amino acid change is novel.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no data on de novo occurrence is available. Therefore, PS2 is not applied due to lack of de novo evidence.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: functional studies demonstrate that ASXL1 truncating mutations lead to loss of the PHD domain, contribute to oncogenesis, and in murine models cause myelodysplastic syndrome. Therefore, PS3 is applied at Strong strength because well-established studies show a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: no case-control or cohort data demonstrating increased prevalence in affected versus controls. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: no specific evidence that c.1927del lies in a defined hotspot or domain beyond general truncation. Therefore, PM1 is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: extremely rare in gnomAD (MAF = 0.0286%, 61/213,340 alleles). Therefore, PM2 is applied at Moderate strength because of its rarity in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: no data on trans configuration in a recessive context. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: this is a frameshift leading to premature truncation, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: '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 not a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: '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. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product.' The evidence for this variant shows: computational analyses including SpliceAI (score 0.02) do not predict impact, and the variant’s effect is established by truncation rather than computational prediction. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or family history data provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: no such external report. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder.' The evidence for this variant shows: MAF 0.0286% is below any BA1 threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder.' The evidence for this variant shows: MAF 0.0286% is below expected thresholds. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age.' The evidence for this variant shows: no reports in healthy individuals. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: segregation data are unavailable. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease.' The evidence for this variant shows: it is a frameshift. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant.' The evidence for this variant shows: no such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function.' The evidence for this variant shows: it is a frameshift outside repetitive regions. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact.' The evidence for this variant shows: computational data are limited and the variant effect is established by truncation. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence.' The evidence for this variant shows: no such report exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: it is not synonymous. Therefore, BP7 is not applied.