NM_015338.5:c.3802A>G

ASXL1 · NP_056153.2:p.(Thr1268Ala) · NM_015338.5

GRCh37: chr20:31024317 A>G · GRCh38: chr20:32436514 A>G

Gene: ASXL1 Transcript: NM_015338.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ASXL1

Transcript

NM_015338.5

Protein

NP_056153.2:p.(Thr1268Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The ASXL1 c.3802A>G (p.Thr1268Ala) variant has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

Available computational evidence supports a benign effect, with REVEL 0.098, BayesDel -0.440581, and SpliceAI showing no predicted splice impact with a maximum delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	Not met	ASXL1 loss of function is an established disease mechanism, but this variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1 or 2 splice variant, and the generic PVS1 framework does not support applying PVS1 to this change.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified that the same amino acid change has already been established as pathogenic by a different nucleotide change.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study was identified for this variant, so functional evidence supporting a damaging effect is not available.	oncokb
PS4	Not met	This variant has only limited observation data, with one ClinVar submission and no case-control or enrichment evidence, so increased prevalence in affected individuals has not been shown.	clinvar
PM1	Not met	Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 cutoff of 0.1% and supports rarity in population databases.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic variant in an established recessive disease context.	clinvar
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 is not applicable.
PM5	Not assessed	No evidence was identified that a different missense change at codon 1268 has already been established as pathogenic.	clinvar
PM6	Not assessed	No presumed de novo occurrence without confirmed parentage was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	Available evidence does not establish that ASXL1 missense variation is a common disease mechanism with a low rate of benign missense variation, so PP2 was not applied.	pvs1_gene_context
PP3	Not met	Available computational evidence does not support a damaging effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI shows no predicted splice impact with a maximum delta score of 0.00.	revel bayesdel spliceai
PP4	Not assessed	No individual-level phenotype data were identified to show a highly specific clinical presentation for a single genetic etiology.
PP5	Not assessed	No reputable source classified this variant as pathogenic, and the available ClinVar entry is uncertain significance rather than a pathogenic assertion supporting PP5.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the benign stand-alone threshold of greater than 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the benign strong threshold of greater than 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient to argue against disease causation.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing a normal or benign effect for this variant.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	Not assessed	ASXL1 loss of function is an established disease mechanism, but the currently reviewed evidence is not sufficient by itself to determine whether missense variation in this gene should be down-weighted under BP1 for this specific interpretation.	pvs1_gene_context
BP2	Not assessed	No phase information was identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis for any relevant disorder context.
BP3	N/A	This is not an in-frame deletion or insertion within a repetitive region, so BP3 is not applicable.
BP4	Met	Multiple computational results support a benign effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.	revel bayesdel spliceai
BP5	Not assessed	No evidence was identified that an alternate molecular cause fully explains an observed phenotype independent of this variant.
BP6	Not assessed	No reputable source classified this variant as benign or likely benign. The available ClinVar entry is uncertain significance.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.