NM_015338.5:c.2694G>A (p.Trp898Ter) is a nonsense variant in exon 13 of 13 in ASXL1, a gene for which loss of function is an established disease mechanism.1 Under ClinGen SVI PVS1 recommendations (PMC6185798), the variant is located in the terminal exon and is not expected to undergo nonsense-mediated decay; PVS1 is applied at moderate strength.2 The variant is extremely rare in population databases with an allele frequency of 3.98 × 10⁻⁶ in gnomAD v2.1 and 1.24 × 10⁻⁶ in gnomAD v4.1, meeting PM2 at supporting level.3 No additional pathogenic or benign criteria were met; the variant is absent from ClinVar, no variant-specific functional studies exist, and no segregation or de novo data are available.4 Based on generic ACMG/AMP 2015 combination rules, one moderate criterion (PVS1_Moderate) and one supporting criterion (PM2_Supporting) are met, yielding a classification of Likely Pathogenic.5
ASXL1
Final classification
VUS
PVS1PM2
ASXL1
c.2694G>A
p.Trp898Ter
This variant
NM_015338.5:c.2694G>A (p.Trp898Ter) is a nonsense variant in exon 13 of 13 in ASXL1, a gene for which loss of function is an established disease mechanism.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
ASXL1 c.2694G>A
PVS1 + PM2
→
VUS
1
pvs1_generic_framework ↗pvs1_gene_context
2
pvs1_generic_framework ↗pvs1_variant_assessment
5
generic_acmg_combination_rules
Gene diagram
· NM_015338.5 · variants mapped to exon structure
ASXL1
NM_015338.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
moderate
Pathogenic
NM_015338.5:c.2694G>A is a nonsense variant predicted to introduce a premature termination codon at residue 898 (p.Trp898Ter). ASXL1 loss of function is an established disease mechanism for Bohring-Opitz syndrome (germline) and myeloid malignancies. Under ClinGen SVI PVS1 recommendations (PMC6185798), nonsense variants in the last exon are not expected to undergo NMD and are downgraded. This variant resides in exon 13 (the final exon) and removes the C-terminal 644 amino acids of the 1542-residue protein; the functional significance of the truncated region is uncertain, warranting PVS1 at moderate strength.
Nonsense variant p.Trp898Ter in the last exon (exon 13 of 13)ASXL1 loss-of-function mechanism supported by germline disease association (Bohring-Opitz syndrome)No NMD expected per PMC6185798 due to location in the terminal exon
✓
PM2
supporting
Pathogenic
NM_015338.5:c.2694G>A is extremely rare in population databases, with an allele frequency far below the 0.1% PM2 threshold. gnomAD v2.1 reports 1 allele in 251,448 (AF = 3.98 × 10⁻⁶) and gnomAD v4.1 reports 2 alleles in 1,614,068 (AF = 1.24 × 10⁻⁶), with zero homozygotes in both datasets.
gnomAD v2.1: 1/251448 alleles (AF = 3.98 × 10⁻⁶)0 homozygotes
Assessed · not applied
· 19 not met · 0 not assessed
Pathogenic
PS1
No alternative nucleotide change producing the same p.Trp898Ter amino acid alteration has been reported as pathogenic.
PS2
No de novo occurrence of NM_015338.5:c.2694G>A has been reported in any patient.
PS3
No well-established functional studies directly assess the biological effect of the specific p.Trp898Ter variant.
PS4
No case-control study or statistically significant enrichment of NM_015338.5:c.2694G>A in affected individuals compared to population controls has been reported.
PM1
NM_015338.5:c.2694G>A (p.Trp898Ter) does not lie within a statistically significant mutational hotspot.
PM6
No de novo observation of NM_015338.5:c.2694G>A has been reported, with or without confirmation of paternity and maternity.
PP1
No segregation data are available for NM_015338.5:c.2694G>A in affected families.
PP3
In silico evidence for a deleterious effect is limited and does not meet the PP3 threshold requiring multiple independent lines of computational support.
PP4
No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for an ASXL1-related disorder.
PP5
No reputable germline source (ClinVar, clinical diagnostic laboratory, or expert panel) has classified NM_015338.5:c.2694G>A as pathogenic.
Benign
BA1
NM_015338.5:c.2694G>A has an allele frequency far below the 1% BA1 threshold.
BS1
NM_015338.5:c.2694G>A has an allele frequency far below the 0.3% BS1 threshold.
BS2
No data are available documenting that NM_015338.5:c.2694G>A has been observed in a healthy adult individual in a pattern inconsistent with the disease penetrance model (e.g., homozygous for a dominant disorder).
BS3
No well-established functional studies demonstrate that NM_015338.5:c.2694G>A (p.Trp898Ter) has no damaging effect on protein function or splicing.
BS4
No segregation data are available to assess non-segregation of NM_015338.5:c.2694G>A with disease in affected families.
BP2
No data are available demonstrating that NM_015338.5:c.2694G>A has been observed in trans with a pathogenic variant for a dominant disorder, or in cis with a known pathogenic variant for a recessive disorder.
BP4
Multiple lines of computational evidence do not convincingly suggest a benign impact.
BP5
No data are available indicating that NM_015338.5:c.2694G>A has been observed in a case where an alternative molecular cause for disease was identified.
BP6
No reputable source has classified NM_015338.5:c.2694G>A as benign or likely benign.
N/A · 5
PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.23911e-06; MAF= 0.00012%, 2/1614068 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69489e-06; MAF= 0.00017%, 2/1180016 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97697e-06; MAF= 0.00040%, 1/251448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7909e-06; MAF= 0.00088%, 1/113754 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,614,068
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,180,016 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,448
0 hom
0 hom
European (non-Finnish) 1 / 113,754 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
19388938 ↗
Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.
ONCOKB
21455215 ↗
Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms.
ONCOKB
22897849 ↗
ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.
ONCOKB
24216483 ↗
Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations.
ONCOKB
26095772 ↗
Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex.
ONCOKB