ASXL1 c.3202C>T, p.Arg1068Ter
NM_015338.5:c.3202C>T
COSMIC ID: COSM41715, COSM6966028
Pathogenic
The c.3202C>T (R1068*) variant in ASXL1 is a truncating null change in a gene where loss of function is established as disease mechanism, supported by Very Strong PVS1, Strong PS3 functional data, Moderate PM2 population rarity, and Supporting PP5, leading to a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
BP4
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.3202C>T
Protein Change
R1068*
Location
Exon 13
(Exon 13 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM41715, COSM6966028
Variant interpretation based on transcript NM_015338.6
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HGVS InputNM_015338:c.3202C>T
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
European (Finnish)
0.00462%
Rare
Global: 0.000796%
European (Finnish): 0.00462%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251322Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 2/251322 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.00462%, 1/21644 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
COSMIC ID
COSM41715, COSM6966028
Recurrence
21 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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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
Functional Summary
The ASXL1 R1068* variant is a truncating mutation in a tumor suppressor gene, leading to the loss of the PHD domain. Functional studies have shown that expression of ASXL1 truncating mutations in murine myeloid cells results in dedifferentiation and myelodysplastic syndrome in a bone marrow transplant mouse model, supporting a damaging effect.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 8.70
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease'. The evidence for this variant shows: the c.3202C>T change introduces a premature stop codon (R1068*) in ASXL1, resulting in loss of function. Therefore, this criterion is applied at Very Strong strength because it is a truncating null variant in a gene with established LoF mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: there is no different nucleotide change reported that results in the same R1068* amino acid change. Therefore, this criterion is not applied.
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 are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: in vivo murine myeloid cell studies demonstrate that truncating ASXL1 mutations (including R1068*) lead to dedifferentiation and myelodysplastic syndrome. Therefore, this criterion is applied at Strong strength because functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls'. The evidence for this variant shows: no case-control data or enrichment in affected cohorts reported. Therefore, this criterion 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 and/or critical and well-established functional domain without benign variation'. The evidence for this variant shows: no specific mutational hotspot or functional domain annotation is provided beyond loss of the PHD domain. Therefore, this criterion 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: observed at MAF=0.000796% overall and 0.00462% in European (Finnish) in gnomAD with no homozygotes, well below threshold. Therefore, this criterion is applied at Moderate strength because it is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant'. The evidence for this variant shows: no evidence of trans configuration with another pathogenic variant. Therefore, this criterion 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: it is a nonsense change causing truncation rather than an in-frame alteration. Therefore, this criterion 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 before'. The evidence for this variant shows: this is a nonsense variant, 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: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data are available. Therefore, this criterion 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 family segregation data provided. Therefore, this criterion 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 where missense variants are a common mechanism of disease'. The evidence for this variant shows: this is a nonsense variant, not missense. Therefore, this criterion 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: CADD score of 8.70 and SpliceAI score of 0.04, with mixed in silico predictions not supporting a damaging effect. Therefore, this criterion 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 is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
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: ClinVar lists the variant as Pathogenic by a clinical laboratory without primary data. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenicity without accessible evidence.
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 well below thresholds for BA1. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency greater than expected for disorder'. The evidence for this variant shows: frequency is extremely low. Therefore, this criterion 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 healthy carrier data. Therefore, this criterion 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, this criterion 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: no segregation evidence. Therefore, this criterion 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: this is a LoF variant. Therefore, this criterion 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 evidence of cis/trans with another variant. Therefore, this criterion 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: not an in-frame or repetitive region variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: CADD score of 8.70 and SpliceAI score of 0.04 with mixed predictions not supporting impact. Therefore, this criterion is applied at Supporting strength because computational tools suggest minimal effect.
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 diagnosis reported. Therefore, this criterion 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 reputable source reports benign classification. Therefore, this criterion 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: this is a nonsense variant, not synonymous. Therefore, this criterion is not applied.