Classification rationale

BP4 VUS

ASXL1 c.2281G>A

The ASXL1 c.2281G>A (p.Ala761Thr) variant has been reported in ClinVar as Likely benign by a single submitter.¹ This variant is present in gnomAD, with a highest observed South Asian allele frequency of 0.09799% (30/30,616) in v2.1 and 0.09442% (86/91,078) in v4.1, which is below the default BS1 threshold of 0.3% and BA1 threshold of 1.0%.² Computational evidence does not support a damaging effect: REVEL is 0.09, BayesDel is -0.340274, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

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.

Gene diagram · NM_015338.5 · variants mapped to exon structure

ASXL1 NM_015338.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 20 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 · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Multiple computational results support no damaging effect. REVEL is low at 0.09, BayesDel is negative at -0.340274, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00.

REVEL 0.09BayesDel -0.340274SpliceAI max delta 0.00

spliceai ↗

Assessed · not applied · 8 not met · 12 not assessed

Pathogenic

PS1 No evidence was identified that a different nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic classification.

PS2 No confirmed de novo occurrence with parental testing and phenotype details was identified for this variant.

PS3 No well-established functional study showing a damaging effect for this specific variant was identified.

PS4 Available evidence does not show that this variant is enriched in affected individuals compared with controls, and it is present in population databases.

PM1 Available evidence does not support that p.Ala761Thr lies in a well-established mutational hotspot or a critical functional domain without benign variation.

PM2 This variant is present in population databases, including a highest observed South Asian allele frequency of 0.09799% in gnomAD v2.1 and 0.09442% in gnomAD v4.1.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.

PM6 No assumed de novo report without confirmed parentage was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not show that missense variation is a common established disease mechanism for ASXL1, so PP2 was not applied.

PP3 Computational evidence does not support a damaging effect.

PP4 No phenotype-specific evidence was identified showing that the reported clinical presentation is highly specific for a disease caused by ASXL1.

Benign

BA1 Population frequency does not reach the default BA1 threshold of 1.0%.

BS1 Population frequency does not exceed the default BS1 threshold of 0.3%.

BS2 The variant is observed in gnomAD, including one homozygote in v4.1, but the available data do not confirm healthy status, age, or phenotype sufficiently to apply BS2 confidently.

BS3 No well-established functional study showing normal or near-normal function for this variant was identified.

BS4 No non-segregation data were identified for this variant.

BP1 ASXL1-related germline disease is strongly associated with loss-of-function variants, but the available evidence in this case was not considered sufficient on its own to apply BP1.

BP2 No data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP5 No evidence was identified for an alternate molecular explanation for disease in the same individual.

N/A · 7 PVS1 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.57609e-05; MAF= 0.00558%, 90/1614034 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000944246; MAF= 0.09442%, 86/91078 alleles, homozygotes = 1); grpmax FAF= 0.00078238.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000123308; MAF= 0.01233%, 31/251404 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00097988; MAF= 0.09799%, 30/30616 alleles, homozygotes = 0); grpmax FAF= 0.00070517.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0056% · 90 / 1,614,034
1 hom · FAF 0.078%

South Asian 86 / 91,078	0.094% 1 hom
Remaining individuals 2 / 62,486	0.0032%
African/African American 2 / 74,916	0.0027%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.012% · 31 / 251,404
0 hom · FAF 0.071%

South Asian 30 / 30,616	0.098%
African/African American 1 / 16,240	0.0062%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1948898)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.09. BayesDel score = -0.340274.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ASXL1, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types, most frequently in myeloid malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60105533, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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