Variant classification summary

NM_015338.6:c.1934dup

ASXL1 · NP_056153.2:p.(Gly646TrpfsTer12) · NM_015338.6

GRCh37: chr20:31022441 A>AG · GRCh38: chr20:32434638 A>AG

Gene: ASXL1 Transcript: NM_015338.6

Final call

Likely Pathogenic

PVS1 strong PS3 supporting PS4 supporting PM6 supporting

Variant details

Gene

ASXL1

Transcript

NM_015338.6

Protein

NP_056153.2:p.(Gly646TrpfsTer12)

gnomAD AF

0.0004276497741884331 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 Strong: c.1934dup creates a truncating ASXL1 allele, downgraded for terminal-exon NMD escape.

2

PS3 Supporting: the exact p.G646Wfs*12 construct altered ASXL1-BAP1 activity in cells.

3

PS4 Supporting: 33/333 cases versus gnomAD controls produced OR 128.50 with CI excluding 1.0.

4

PM6 Supporting: seven ClinVar submissions report de novo origin without confirmed maternity and paternity.

Final determination: Generic ACMG/AMP 2015 rules classify the variant as Likely Pathogenic when 1 Strong pathogenic criterion is combined with at least 2 Supporting pathogenic criteria; PVS1 Strong plus PS3, PS4, and PM6 Supporting satisfies this rule.

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 at strong: c.1934dup causes p.G646Wfs*12 in terminal exon 13, so predicted NMD escape triggers the named downgrade from very strong PVS1.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:25741868 PMID:26095772 PMID:31076447
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: de novo origin is reported, but both maternity and paternity confirmation for the proband are not documented.	clinvar
PS3	Met	Met at supporting: the exact p.G646Wfs*12 construct substantially enhanced BAP1 H2AK119Ub deubiquitinase activity versus full-length ASXL1 in cells.	PMID:26095772
PS4	Met	Met: 33/333 cases versus approximately 685/800,889 gnomAD controls gives OR 128.50 (95% CI 89.01-185.51), exceeding OR >5.0 with CI excluding 1.0.	PMID:31076447 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Not met	Not met: the variant is present at AF 0.00042765 in gnomAD v4.1, exceeding the generic PM2 cutoff of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no parent-tested phase or pathogenic variant in trans is documented for this exact ASXL1 variant.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Met	Met at supporting strength: seven ClinVar submissions report de novo origin, without documented confirmation of both maternity and paternity.	clinvar
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or familial variant-status results are documented for co-segregation.	clinvar
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: this frameshift variant is outside PP3's missense and intronic/synonymous/splice-region computational-evidence scope.
PP4	Not assessed	Not assessed: the available case-report lead names Bohring-Opitz syndrome but lacks detailed phenotype evidence establishing high specificity.
PP5	Not met	Not met: the exact variant has 0 ClinVar expert-panel submissions, so laboratory and non-expert pathogenic assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD grpmax FAF is 0.00042259, far below the generic BA1 threshold of 0.05, and the ClinVar consensus is pathogenic/likely pathogenic.	gnomad_v2 gnomad_v4 clinvar
BS1	Not met	Not met: the highest qualifying grpmax FAF is 0.00055108, below the generic BS1 default threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but does not provide a confirmed, phenotyped healthy-adult carrier observation for this artifact-prone indel.	gnomad_v2 gnomad_v4 PMID:31076447
BS3	Not met	Not met: p.G646Wfs*12 altered ASXL1-BAP1 activity, enhancing H2AK119Ub deubiquitinase activity rather than showing no damaging effect.	PMID:26095772
BS4	Not assessed	Not assessed: no affected relatives with negative variant testing or other documented non-segregation evidence are available.	clinvar
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no pathogenic variant in trans or cis is documented for an affected proband carrying this exact ASXL1 variant.	clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: a frameshift's SpliceAI max delta 0.015 cannot support BP4 because the protein-length-changing variant remains impactful by consequence.
BP5	Not met	Not met: no case documents this exact variant together with an alternate molecular basis for the disease.
BP6	Not met	Not met: ClinVar reports 0 expert-panel submissions and no exact-variant expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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.