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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -466 bp |
| Donor Loss (DL) | 0.0 | -13 bp |
| Acceptor Gain (AG) | 0.0 | -216 bp |
| Donor Gain (DG) | 0.0 | 56 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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 or multi-exon deletion in a LoF gene)". The evidence for this variant shows: a missense change (M1050V) rather than a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not result in a predicted loss of function.
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 previously established pathogenic variant results in M1050V. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid 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 on de novo status. Therefore, this criterion is not applied at Not Applied strength because de novo confirmation is unavailable.
PS3 (Not Applied)
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: no functional assays have been performed. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
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 prevalence data in affected cohorts. Therefore, this criterion is not applied at Not Applied strength because case prevalence information is missing.
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 information placing M1050V in a known hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not located in a characterized hot spot or domain.
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 = 0.0099% in gnomAD, with no homozygotes, representing an extremely low population frequency. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in control 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: no data on phase with other variants. Therefore, this criterion is not applied at Not Applied strength because allelic phase information is unavailable.
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: M1050V is a missense substitution without length change. Therefore, this criterion is not applied at Not Applied strength because there is no alteration to protein length.
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: no pathogenic missense variants reported at codon 1050. Therefore, this criterion is not applied at Not Applied strength because no other pathogenic missense change has been observed at this residue.
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 or parental confirmation data. Therefore, this criterion is not applied at Not Applied strength because assumed de novo status cannot be assessed.
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 at Not Applied strength because segregation information is lacking.
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: ASXL1 disease mechanism is primarily loss of function and missense variants are not a common pathogenic mechanism. Therefore, this criterion is not applied at Not Applied strength because the gene is not characterized by pathogenic missense variation.
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 (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico tools including SpliceAI predict no impact on protein function or splicing. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support deleterious effect.
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 patient phenotype or family history provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be evaluated.
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 other reputable sources. Therefore, this criterion is not applied at Not Applied strength because no reputable pathogenic assertion is available.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF = 0.0099%, which is well below thresholds for BA1. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not incompatible with disease.
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 < 0.1%, not exceeding expected disease frequency. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not greater than expected.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: no data on healthy adult observations or penetrance. Therefore, this criterion is not applied at Not Applied strength because healthy adult data are unavailable.
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: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional assay data are lacking.
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 familial segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation information is unavailable.
BP1 (Supporting)
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: ASXL1 pathogenic mechanism is loss of function and M1050V is a missense change. Therefore, this criterion is applied at Supporting strength because the gene’s disease mechanism is exclusively LoF.
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 data on co-occurrence with other variants. Therefore, this criterion is not applied at Not Applied strength because phase information is unavailable.
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: M1050V is a single amino acid substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant type does not match.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: in silico tools including SpliceAI predict no impact on splicing or protein function. Therefore, this criterion is applied at Supporting strength because computational analyses consistently predict no 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 cases reported with an alternate molecular cause. Therefore, this criterion is not applied at Not Applied strength because no relevant case data are available.
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: not reported as benign by any reputable source. Therefore, this criterion is not applied at Not Applied strength because no benign assertions exist.
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: M1050V is a missense substitution, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.