NM_004656.4:c.1081_1084del (p.Leu361ThrfsTer68) is a frameshift deletion in exon 11 of BAP1, predicted to cause nonsense-mediated decay and loss of protein function. BAP1 loss of function is an established mechanism for BAP1 tumor predisposition syndrome.1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting its rarity in the general population.2 This variant is absent from ClinVar and has not been previously reported in the literature with variant-specific evidence.3 SpliceAI predicts no significant splicing impact (max delta 0.09), and in silico missense predictors are not applicable to this deletion variant.4 No variant-specific functional studies, segregation data, or de novo observations were identified. Two BAP1-focused publications (PMID:18757409, PMID:21874000) were reviewed in full text; neither mentions NM_004656.4:c.1081_1084delCTAG.5
BAP1
Final classification
Likely Pathogenic
PVS1PM2
BAP1
c.1081_1084del
p.Leu361ThrfsTer68
This variant
NM_004656.4:c.1081_1084del (p.Leu361ThrfsTer68) is a frameshift deletion in exon 11 of BAP1, predicted to cause nonsense-mediated decay and loss of protein function. BAP1 loss of function is an established mechanism for BAP1 tumor predisposition syndrome.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
BAP1 c.1081_1084del
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
Gene diagram
· NM_004656.4 · variants mapped to exon structure
BAP1
NM_004656.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_004656.4:c.1081_1084del is a 4-bp frameshift deletion in exon 11 of 17, predicted to produce NP_004647.1:p.(Leu361ThrfsTer68) with a premature termination codon in exon 12, well upstream of the last exon-exon junction. Nonsense-mediated decay is expected. BAP1 loss of function is an established disease mechanism for BAP1 tumor predisposition syndrome (BAP1-TPDS). Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant with predicted NMD in a gene where LOF is a known mechanism qualifies for PVS1 at very strong strength.
Frameshift deletion c.1081_1084del in exon 11/17PTC in exon 12Predicted NMD-competent: PTC occurs before last exon-exon junction
✓
PM2
moderate
Pathogenic
NM_004656.4:c.1081_1084del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0.0 in all population databases queried. Under generic ACMG/AMP rules, absence from large population cohorts meets PM2 at moderate strength.
Absent from gnomAD v2.1 (AF=0)Absent from gnomAD v4.1 (AF=0)Absent from gnomAD-Canada v1.0 (AF=0)
Assessed · not applied
· 5 not met · 13 not assessed
Pathogenic
PS2
No de novo data with confirmed paternity/maternity are available for this variant.
PS3
No variant-specific functional studies were identified for NM_004656.4:c.1081_1084delCTAG.
PS4
No case-control prevalence data are available for this variant.
PM1
This variant does not lie within a statistically significant mutational hotspot (CancerHotspots.org) and is not located within a well-characterized functional domain without benign variation per available evidence.
PM6
No reported de novo observation (with or without confirmed paternity/maternity) for this variant.
PP1
No cosegregation data are available for this variant.
PP3
SpliceAI predicts no significant splice impact (max delta score = 0.09), which is below the commonly applied pathogenic threshold of 0.2.
PP4
No patient phenotype or family history data are available for assessment.
PP5
This variant is absent from ClinVar; no reputable source has reported it as pathogenic with unavailable evidence.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from all population databases queried.
BS2
No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3
No functional studies demonstrating no damaging effect for this variant are available.
BS4
No segregation data in affected families are available to assess lack of cosegregation.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant in a recessive disorder.
BP4
SpliceAI max delta score of 0.09 is low but does not constitute multiple lines of computational evidence suggesting no impact on gene product.
BP5
No data are available showing this variant in a case with an established alternate molecular basis for disease.
BP6
This variant is absent from ClinVar; no reputable source has reported it as benign with unavailable evidence.
N/A · 7
PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
18757409 ↗
BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
ONCOKB