Variant classification summary

NM_015338.5:c.2148dupT

ASXL1 · NP_056153.2:p.(Arg717Ter) · NM_015338.5

GRCh37: chr20:31022662 C>CT · GRCh38: chr20:32434859 C>CT

Gene: ASXL1 Transcript: NM_015338.5

Final call

VUS

PVS1 moderate PM2 supporting BP4 supporting

Variant details

Gene

ASXL1

Transcript

NM_015338.5

Protein

NP_056153.2:p.(Arg717Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Moderate): last-exon nonsense escapes nonsense-mediated decay but truncates ~54% of the protein, exceeding the >10% consequential-truncation threshold.

2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

3

BP4 (Supporting): SpliceAI max delta 0.018, below the 0.2 splice-altering threshold.

4

Overall: VUS - met criteria (PVS1 Moderate, PM2 Supporting, BP4 Supporting) combine under no ACMG/AMP 2015 rule.

Final determination: Generic ACMG/AMP 2015 fallback: PVS1-Moderate + PM2-supporting + BP4-supporting satisfies no pathogenic, likely pathogenic, benign, or likely benign combination, yielding VUS.

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	Met	Met (Moderate): last-exon stop codon escapes nonsense-mediated decay but removes 54% of the protein, exceeding the >10% truncation threshold.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework oncokb spliceai
PS1	N/A	Not applicable: a nonsense variant creates no altered amino acid to compare against an established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotypes or de novo occurrence data were available.	final_classification_framework
PS3	Not assessed	Not assessed: no validated functional assay of this exact variant was available.
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data for this variant were available.
PM1	N/A	Not applicable: no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband with this variant in trans with a pathogenic ASXL1 variant was identified.	final_classification_framework
PM4	N/A	Not applicable: nonsense variant causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing data were available to confirm an assumed de novo occurrence.	final_classification_framework
PP1	Not assessed	Not assessed: no family pedigree or segregation data were available.	final_classification_framework
PP2	N/A	Not applicable: missense-specific criterion; no missense change is present in this variant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.018, far below the 0.2 splice-altering threshold.	spliceai
PP4	Not assessed	Not assessed: no phenotype or diagnostic context for the tested individual was provided.
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic assertion for this variant was identified.	clinvar
BA1	Not met	Not met: variant absent from gnomAD, so no allele frequency approaches the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from population datasets, with no allele frequency exceeding that expected for an ASXL1-related disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: population data show absence only, with no healthy-carrier observations available.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay of this exact variant was available to show lack of damaging effect.
BS4	Not assessed	Not assessed: no genotype-phenotype data for relatives were available.	final_classification_framework
BP1	N/A	Not applicable: primarily-truncating-disease criterion for missense variants; no missense change is present.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of the variant in cis or trans with an independent pathogenic ASXL1 variant was provided.	final_classification_framework
BP3	N/A	Not applicable: no in-frame change in a repetitive region; a stop codon alters the protein sequence.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.018, far below the 0.2 splice-altering cutoff.	spliceai
BP5	Not assessed	Not assessed: no alternate molecular diagnosis or phenotype attribution was provided.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign assertion for this variant was identified.	clinvar
BP7	N/A	Not applicable: nonsense variant alters the protein sequence, so the silent-variant criterion does not apply.	generic_acmg_combination_rules

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