Variant classification summary

NM_015338.5:c.2281G>A

ASXL1 · NP_056153.2:p.(Ala761Thr) · NM_015338.5

GRCh37: chr20:31022796 G>A · GRCh38: chr20:32434993 G>A

Gene: ASXL1 Transcript: NM_015338.5

Final call

VUS

BP4 supporting

Variant details

Gene

ASXL1

Transcript

NM_015338.5

Protein

NP_056153.2:p.(Ala761Thr)

gnomAD AF

5.576090714322003e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

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%.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1 or 2 splice-site variant, so the generic PVS1 loss-of-function framework does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence was identified that a different nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic classification.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental testing and phenotype details was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study showing a damaging effect for this specific variant was identified.	oncokb
PS4	Not met	Available evidence does not show that this variant is enriched in affected individuals compared with controls, and it is present in population databases.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not support that p.Ala761Thr lies in a well-established mutational hotspot or a critical functional domain without benign variation.	hotspots
PM2	Not met	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. Although these values are below the default 0.1% PM2 cutoff, the variant is observed recurrently in population datasets and was not treated as convincingly rare for ACMG PM2 evidence.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change or in-frame insertion or deletion.
PM5	N/A	Classic same-residue PM5 semantics could not be confirmed safely for this case, and no qualifying pathogenic comparator variants were identified.	pm5_candidates
PM6	Not assessed	No assumed de novo report without confirmed parentage was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not met	Available evidence does not show that missense variation is a common established disease mechanism for ASXL1, so PP2 was not applied.	pvs1_gene_context
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	No phenotype-specific evidence was identified showing that the reported clinical presentation is highly specific for a disease caused by ASXL1.
PP5	N/A	PP5 was not applied because no qualifying reputable-source pathogenic assertion independent of the underlying evidence review was identified.	clinvar
BA1	Not met	Population frequency does not reach the default BA1 threshold of 1.0%. The highest observed population frequency is 0.09799% in gnomAD v2.1 and 0.09442% in gnomAD v4.1, both below 1.0%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the default BS1 threshold of 0.3%. The highest observed population frequency is 0.09799% in gnomAD v2.1 and 0.09442% in gnomAD v4.1, both below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	No well-established functional study showing normal or near-normal function for this variant was identified.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	Not assessed	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.	pvs1_gene_context
BP2	Not assessed	No data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP3	N/A	This variant is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation for disease in the same individual.
BP6	N/A	BP6 was not applied because the available ClinVar entry is a single-submitter likely benign assertion and does not meet a separate reputable-source criterion for benign classification without independent evidence review.	clinvar
BP7	N/A	This variant is missense rather than synonymous, so BP7 does not apply.

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