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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The ASXL1 G643Wfs*15 variant is a truncating mutation that results in the loss of the PHD domain, leading to the production of C-terminally truncated proteins. Functional studies have shown that expression of ASXL1 truncating mutations in murine myeloid cells causes 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) | 0.0 | -206 bp |
| Donor Loss (DL) | 0.02 | -57 bp |
| Acceptor Gain (AG) | 0.0 | 143 bp |
| Donor Gain (DG) | 0.0 | 439 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: NM_015338.5:c.1926_1927insT is a frameshift variant predicted to truncate the ASXL1 protein and remove the PHD domain, consistent with LoF. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a gene where LoF is a known disease mechanism.
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: there is no reported variant producing the same G643Wfs*15 protein change by a different nucleotide alteration. Therefore, this criterion is not applied because no identical amino acid change has been observed from another nucleotide change.
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 are available regarding de novo occurrence. Therefore, this criterion is not applied due to lack of confirmed de novo evidence.
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 studies of ASXL1 truncating mutations demonstrate dedifferentiation and myelodysplastic syndrome, indicating a damaging effect. Therefore, this criterion is applied at Strong strength because functional studies support a deleterious effect of the truncation.
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 frequency data or statistical enrichment in affected cohorts. Therefore, this criterion is not applied due to absence of prevalence data.
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: exon and domain localization relative to known hot spots is not established. Therefore, this criterion is not applied because hotspot/domain information is insufficient.
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% in gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
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: no data on trans configuration in a recessive context. 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 frameshift leading to premature stop, already captured by PVS1. 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: it is not a missense change. 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 information on parental origin. 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 family 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: it is a truncating variant. 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/gene product." The evidence for this variant shows: CADD score of 7.17 and SpliceAI max score of 0.02, indicating minimal impact computationally. 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 clinical details provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
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: not reported in ClinVar or similar databases. Therefore, this criterion is not applied.
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%. 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: MAF = 0%. 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 such observations. 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 effects. 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 frameshift LoF 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 frameshift, not an in-frame 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 of 7.17 and SpliceAI score of 0.02, indicating minimal predicted impact. Therefore, this criterion is applied at Supporting strength because computational analyses do not predict a deleterious effect.
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 alternate molecular basis reported. 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 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 frameshift variant. Therefore, this criterion is not applied.