0%
ASXL1c.2694G>AUncertain significance
Print report
Variant interpretation report

ASXL1 c.2694G>A, p.(Trp898Ter)

NM_015338.5:c.2694G>A NP_056153.2:p.(Trp898Ter) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ASXL1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Moderate
PVS1 · moderate

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,614,068 alleles

gnomAD v4.1: 2 / 1,614,068 alleles. Recorded AF 1.23911e-06. Recorded homozygote count 0.

gnomAD 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).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

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.

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.

Met · 2

PVS1 ModerateNM_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. Details ▾Hide ▴
Evidence considered
  • 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
  • C-terminal truncation removes ~42% of protein
  • functional significance of distal region is uncertain
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1/251
  • 448 alleles (AF = 3.98 × 10⁻⁶)
  • 0 homozygotes
  • gnomAD v4.1: 2/1
  • 614
  • 068 alleles (AF = 1.24 × 10⁻⁶)
  • Both far below generic ACMG PM2 threshold of 0.1%
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 20 · evaluated, threshold not reached

PS1 No alternative nucleotide change producing the same p.Trp898Ter amino acid alteration has been reported as pathogenic. ClinVar contains no entry for this variant or any other W898* variant. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no established pathogenic variant at the same codon via a different nucleotide change
Sources
clinvar ↗
PS2 No de novo occurrence of NM_015338.5:c.2694G>A has been reported in any patient. No published case report or ClinVar submission documents a de novo observation of this variant. Details ▾Hide ▴
Evidence considered
  • No de novo report in ClinVar or published literature
Still missing
  • No proband-level data available to assess de novo status
Sources
clinvar ↗
PS3 No well-established functional studies directly assess the biological effect of the specific p.Trp898Ter variant. Five publications discuss ASXL1 truncations in general and support loss-of-function as a disease mechanism in somatic myeloid malignancies, but none experimentally characterize NM_015338.5:c.2694G>A. Details ▾Hide ▴
Evidence considered
  • Five publications reviewed discuss ASXL1 truncations broadly but do not mention c.2694G>A or p.Trp898Ter
Still missing
  • No variant-specific functional assay data (e.g.
  • luciferase reporter
  • DUB activity
  • histone methylation readout) for p.Trp898Ter
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. The variant is absent from ClinVar and no proband counts are available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar with zero clinical assertions
  • gnomAD population frequency is extremely low (1–2 alleles across >1.8 million chromosomes)
  • insufficient for PS4 case-control analysis
Still missing
  • No proband cohort data available
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
PM1 NM_015338.5:c.2694G>A (p.Trp898Ter) does not lie within a statistically significant mutational hotspot. Although ASXL1 truncating mutations cluster broadly across exons 12–13, residue 898 is not a recurrently mutated codon in the hotspot analysis. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not in a statistically significant hotspot
  • exact variant not listed as recurrent
Sources
clinvar ↗
PM6 No de novo observation of NM_015338.5:c.2694G>A has been reported, with or without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
  • No de novo report in ClinVar or literature
Still missing
  • No proband-level data
Sources
clinvar ↗
PP1 No segregation data are available for NM_015338.5:c.2694G>A in affected families. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP3 In silico evidence for a deleterious effect is limited and does not meet the PP3 threshold requiring multiple independent lines of computational support. SpliceAI predicts no splicing impact (max delta = 0.01). BayesDel scores 0.66, marginally above the 0.5 threshold, but REVEL and HCI prior scores are unavailable for this variant. A single borderline in silico predictor is insufficient to invoke PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no predicted splice alteration)
  • BayesDel = 0.66 (weakly above 0.5 threshold)
  • REVEL not available
  • HCI prior not available
Still missing
  • No REVEL score available
  • No HCI prior probability available
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for an ASXL1-related disorder. Details ▾Hide ▴
Still missing
  • No proband phenotype data available
PP5 No reputable germline source (ClinVar, clinical diagnostic laboratory, or expert panel) has classified NM_015338.5:c.2694G>A as pathogenic. The OncoKB annotation of Likely Oncogenic applies to a somatic cancer context and does not satisfy PP5 for germline variant interpretation. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • OncoKB Likely Oncogenic is a somatic annotation
  • not equivalent to a germline pathogenic classification
Sources
clinvar ↗oncokb ↗
BA1 NM_015338.5:c.2694G>A has an allele frequency far below the 1% BA1 threshold. The highest population sub-frequency is 8.79 × 10⁻⁶ in gnomAD v2.1 European (non-Finnish). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF = 3.98 × 10⁻⁶ (0.0004%)
  • gnomAD v4.1 total AF = 1.24 × 10⁻⁶ (0.00012%)
  • Both far below BA1 threshold of 1%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_015338.5:c.2694G>A has an allele frequency far below the 0.3% BS1 threshold. The variant is observed in only 1–2 alleles across >1.8 million chromosomes in gnomAD. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF = 3.98 × 10⁻⁶
  • gnomAD v4.1 total AF = 1.24 × 10⁻⁶
  • Both far below BS1 threshold of 0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗
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). Details ▾Hide ▴
Still missing
  • No clinical or phenotype data available for the single gnomAD carrier
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. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available
BS4 No segregation data are available to assess non-segregation of NM_015338.5:c.2694G>A with disease in affected families. Details ▾Hide ▴
Still missing
  • No family segregation data available
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. Details ▾Hide ▴
Still missing
  • No phasing data available
BP4 Multiple lines of computational evidence do not convincingly suggest a benign impact. While SpliceAI predicts no splicing alteration (delta = 0.01), BayesDel scores 0.66, which is above the 0.5 threshold favoring a deleterious interpretation. The in silico evidence is conflicting rather than consistently benign. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splicing impact)
  • BayesDel = 0.66 (above 0.5
  • weakly predicts deleterious effect)
Sources
spliceai ↗bayesdel
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. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available
BP6 No reputable source has classified NM_015338.5:c.2694G>A as benign or likely benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source
Sources
clinvar ↗
PS5 No reputable source (ClinVar, clinical laboratory, or expert panel) has classified NM_015338.5:c.2694G>A as pathogenic. The variant is absent from ClinVar entirely. OncoKB annotates the variant as Likely Oncogenic in a somatic context, which does not constitute a germline classification. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • OncoKB Likely Oncogenic classification is somatic
  • not a germline ACMG classification
Sources
clinvar ↗oncokb ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 requires a pathogenic missense variant at the same codon. NM_015338.5:c.2694G>A is a nonsense variant, and no same-residue comparator variants were identified in ClinVar. Details ▾Hide ▴
Evidence considered
  • Nonsense variant
  • no pathogenic missense comparators at codon 898 in ClinVar
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_015338.5:c.2694G>A is a nonsense (truncating) variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are a known disease mechanism. NM_015338.5:c.2694G>A is itself a truncating (nonsense) variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_015338.5:c.2694G>A is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants without predicted splice impact. NM_015338.5:c.2694G>A is a nonsense variant, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
ASXL1
Transcript
NM_015338.5
Coding (HGVS c.)
NM_015338.5:c.2694G>A
Protein (HGVS p.)
NP_056153.2:p.(Trp898Ter)
GRCh38
chr20:32435406 G>A
GRCh37
chr20:31023209 G>A

Gene diagram

Every interpreted variant in ASXL1, mapped onto the exon structure of NM_015338.5. Select a row to find it on the plot.

ASXL1NM_015338.5
Fetching transcript structure from UCSC…
gnomAD v4.1 2 / 1,614,068 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1 1 / 251,448 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,614,068 alleles · 0 hom · FAF 2.8e-07
European (non-Finnish)2 / 1,180,016 1.7e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,448 alleles · 0 hom
European (non-Finnish)1 / 113,754 8.8e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD 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).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -12 bp
0.000
SpliceAI acceptor gainat +238 bp
0.000
SpliceAI donor lossat +292 bp
0.010
SpliceAI donor gainat -329 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 In silico evidence for a deleterious effect is limited and does not meet the PP3 threshold requiring multiple independent lines of computational support. SpliceAI predicts no splicing impact (max delta = 0.01). BayesDel scores 0.66, marginally above the 0.5 threshold, but REVEL and HCI prior scores are unavailable for this variant. A single borderline in silico predictor is insufficient to invoke PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no predicted splice alteration)
  • BayesDel = 0.66 (weakly above 0.5 threshold)
  • REVEL not available
  • HCI prior not available
Still missing
  • No REVEL score available
  • No HCI prior probability available
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence do not convincingly suggest a benign impact. While SpliceAI predicts no splicing alteration (delta = 0.01), BayesDel scores 0.66, which is above the 0.5 threshold favoring a deleterious interpretation. The in silico evidence is conflicting rather than consistently benign. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splicing impact)
  • BayesDel = 0.66 (above 0.5
  • weakly predicts deleterious effect)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants without predicted splice impact. NM_015338.5:c.2694G>A is a nonsense variant, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.
    Reports ASXL1 mutations in myelodysplastic syndromes and chronic myelomonocytic leukaemia. NM_015338.5:c.2694G>A (p.Trp898Ter) was not identified in the abstract of this paper.
    Does not name this variant
    PMID 19388938 ↗
  • Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms.
    Analyzes concomitant EZH2 and ASXL1 mutations in myelofibrosis, CMML, and blast-phase MPNs. Discusses ASXL1 nonsense and frameshift mutations generally. NM_015338.5:c.2694G>A (p.Trp898Ter) was not identified in the full text.
    Does not name this variant
    PMID 21455215 ↗
  • ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.
    Demonstrates that ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Characterizes ASXL1 truncating mutations broadly but does not mention NM_015338.5:c.2694G>A (p.Trp898Ter).
    Does not name this variant
    PMID 22897849 ↗
  • Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations.
    Shows that ASXL1 mutations altering histone methylation induce myelodysplastic syndromes in a mouse model. Reports various ASXL1 truncating mutations but does not include NM_015338.5:c.2694G>A (p.Trp898Ter).
    Does not name this variant
    PMID 24216483 ↗
  • Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex.
    Reports that cancer-associated ASXL1 truncating mutations may act as gain-of-function mutations in the ASXL1-BAP1 complex. Examines multiple ASXL1 truncations but does not identify NM_015338.5:c.2694G>A (p.Trp898Ter).
    Does not name this variant
    PMID 26095772 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,614,068 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.