Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_015338.5 | RefSeq Select | 7056 nt | 433–5058 |
| NM_015338.4 | Alternative | 7047 nt | 427–5052 |
| NM_015338.3 | Alternative | 7026 nt | 420–5045 |
| NM_015338.6 | MANE Select | 7052 nt | 446–5071 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change creates a premature translational stop signal (p.Tyr591*) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 951 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 variant has not been reported in the literature in individuals affected with ASXL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2498883). This variant disrupts a region of the ASXL1 protein in which other variant(s) (p.Glu1400*) have been determined to be pathogenic (PMID: 31969346). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The ASXL1 Y591* variant is a truncating mutation in a tumor suppressor gene, leading to the production of C-terminally truncated proteins and 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.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.03 | -53 bp |
| Donor Loss (DL) | 0.02 | 96 bp |
| Acceptor Gain (AG) | 0.0 | 4 bp |
| Donor Gain (DG) | 0.02 | -14 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
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 (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: it is a nonsense variant (Y591*) introducing a premature stop codon, predicted to cause truncation of ASXL1 leading to loss of function. Therefore, this criterion is applied at Very Strong strength because a null variant is present in ASXL1, a gene where LoF is known to cause disease.
PS1 (Not Applied)
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: no alternative nucleotide change at codon 591 yielding the same amino acid change has been reported. Therefore, this criterion is not applied.
PS2 (Not Applied)
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 or parental testing. Therefore, this criterion is not applied.
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: functional studies in murine myeloid cells demonstrate that ASXL1 Y591* causes dedifferentiation and myelodysplastic syndrome in mouse bone marrow transplant models, supporting a damaging effect. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect on the gene product.
PS4 (Not Applied)
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 prevalence data. Therefore, this criterion is not applied.
PM1 (Not Applied)
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 hotspot or domain data. Therefore, this criterion is not applied.
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: MAF=0.000796% in gnomAD with no homozygotes, indicating extreme rarity. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
PM3 (Not Applied)
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: ASXL1-associated disease is dominant and no trans data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
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 variant, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
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: this is a nonsense change, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
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 (Not Applied)
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, this criterion is not applied.
PP2 (Not Applied)
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: this is a nonsense variant, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The evidence for this variant shows: CADD score 9.10 and SpliceAI scores ≤0.03 do not support a deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
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. Therefore, this criterion is not applied.
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 entries list this variant as Likely Pathogenic (1 lab) and Pathogenic (1 lab) without primary evidence. Therefore, this criterion is applied at Supporting strength because reputable sources report it as pathogenic.
BA1 (Not Applied)
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 0.000796% is well below any threshold for BA1. Therefore, this criterion is not applied.
BS1 (Not Applied)
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: frequency is extremely low. Therefore, this criterion is not applied.
BS2 (Not Applied)
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 observations in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
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 (Not Applied)
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 data. Therefore, this criterion is not applied.
BP1 (Not Applied)
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 nonsense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
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 observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
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 nonsense change. Therefore, this criterion is not applied.
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 9.10 and SpliceAI scores ≤0.03 indicate lack of predicted impact. Therefore, this criterion is applied at Supporting strength because computational evidence suggests no impact.
BP5 (Not Applied)
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 such context. Therefore, this criterion is not applied.
BP6 (Not Applied)
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 benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
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 a nonsense variant. Therefore, this criterion is not applied.