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LYFE SCIENCES
Project: HERA
NM_015338.5:c.2281G>A
p.Ala761Thr  ·  ASXL1
ACMG/AMP
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Classification rationale
1

The ASXL1 c.2281G>A (p.Ala761Thr) variant has been reported in ClinVar as Likely benign by a single submitter.

clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1948898)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA761
Hotspots ↗