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 ↗

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

ASXL1 NM_015338.5

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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