NM_004656.4:c.1081_1084delCTAG

BAP1 · NP_004647.1:p.(Leu361ThrfsTer68) · NM_004656.4

GRCh37: chr3:52439157 TCTAG>T · GRCh38: chr3:52405141 TCTAG>T

Gene: BAP1 Transcript: NM_004656.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.(Leu361ThrfsTer68)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting its rarity in the general population.

This variant is absent from ClinVar and has not been previously reported in the literature with variant-specific evidence.

SpliceAI predicts no significant splicing impact (max delta 0.09), and in silico missense predictors are not applicable to this deletion variant.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to missense variants with a same-amino-acid change as a known pathogenic variant. This is a frameshift deletion, not a missense substitution.
PS2	Not assessed	No de novo data with confirmed paternity/maternity are available for this variant.
PS3	Not assessed	No variant-specific functional studies were identified for NM_004656.4:c.1081_1084delCTAG. Two publications (PMID:18757409, PMID:21874000) were reviewed in full text; neither mentions this variant. OncoKB annotation of Likely Oncogenic/Likely Loss-of-function reflects somatic curation and does not constitute independent germline functional evidence sufficient for PS3.
PS4	Not assessed	No case-control prevalence data are available for this variant.
PS5	N/A	PS5 applies when a variant is found in a case with an established alternate molecular basis for disease. No such data are available, and PS5 is only applicable when an alternative explanation is documented.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is an out-of-frame (frameshift) deletion; the predicted protein effect is already captured under PVS1.
PM5	N/A	PM5 applies to a novel missense change at the same amino acid residue as a previously established pathogenic missense variant. This is a frameshift deletion, not a missense substitution, and no structurally comparable comparator variants were identified (see pm5_candidates.json).
PM6	Not assessed	No reported de novo observation (with or without confirmed paternity/maternity) for this variant.
PP1	Not assessed	No cosegregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This is a frameshift deletion, not a missense substitution.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.09), which is below the commonly applied pathogenic threshold of 0.2. REVEL and BayesDel scores are not applicable for deletion variants. No HCI prior probability score is available. Insufficient in silico evidence to support a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available for assessment.
PP5	Not assessed	This variant is absent from ClinVar; no reputable source has reported it as pathogenic with unavailable evidence.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency of 0.0 does not reach the BA1 threshold (>1%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases queried. Allele frequency of 0.0 does not reach the BS1 threshold (>0.3% under generic ACMG rules).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not assessed	No functional studies demonstrating no damaging effect for this variant are available.
BS4	Not assessed	No segregation data in affected families are available to assess lack of cosegregation.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a truncating (frameshift) variant, not a missense substitution.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a pathogenic variant in a recessive disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is an out-of-frame (frameshift) deletion, not an in-frame change.
BP4	Not met	SpliceAI max delta score of 0.09 is low but does not constitute multiple lines of computational evidence suggesting no impact on gene product. The score is insufficient to meet BP4, which requires strong benign computational predictions.	spliceai
BP5	Not assessed	No data are available showing this variant in a case with an established alternate molecular basis for disease.
BP6	Not assessed	This variant is absent from ClinVar; no reputable source has reported it as benign with unavailable evidence.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous substitution.

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