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BAP1c.376_382delUncertain significance
Print report
Variant interpretation report

BAP1 c.376_382del, p.(Ser126AspfsTer59)

NM_004656.4:c.376_382del NP_004647.1:p.(Ser126AspfsTer59) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About BAP1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Frameshift variant NM_004656.4:c.376_382del (p.S126Dfs*59) in BAP1 exon 6 creates a premature termination codon at residue 184 of 730, well upstream of the NMD escape boundary. BAP1 has an established loss-of-function disease mechanism (BAP1 tumor predisposition syndrome). NM_004656.4 is the MANE Select transcript. Under PMC6185798, a frameshift in a gene with confirmed germline LoF mechanism qualifies for PVS1 at full strength.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the non-VCEP PM2 threshold of allele frequency below 0.1%.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
1.000 maximum delta

Recorded SpliceAI maximum delta score: 1.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 14 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 (very strong): NM_004656.4:c.376_382del is a frameshift deletion in BAP1 exon 6, creating a premature termination codon at p.S126Dfs*59 with predicted NMD. BAP1 loss-of-function is the established germline disease mechanism for BAP1 tumor predisposition syndrome (PMID:35051358, PMID:35348477, PMID:39842618). NM_004656.4 is the MANE Select transcript.

PM2 (supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.

Classification: Likely Pathogenic. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PVS1 (Very Strong) is met and PM2 (Supporting) is met. This combination of 1 Very Strong and 1 Supporting criterion does not satisfy the formal threshold for Pathogenic (which requires 1 Very Strong + ≥2 Supporting or ≥1 Strong). However, a frameshift null variant in a gene with established LoF disease mechanism, absent from all population databases, is classified as Likely Pathogenic per clinical practice. Per ACMG/AMP 2015, the evidence falls between formal Likely Pathogenic and Pathogenic thresholds; classification is Likely Pathogenic with a note that additional supporting evidence would elevate to Pathogenic.

Met · 2

PVS1 Very strongFrameshift variant NM_004656.4:c.376_382del (p.S126Dfs*59) in BAP1 exon 6 creates a premature termination codon at residue 184 of 730, well upstream of the NMD escape boundary. BAP1 has an established loss-of-function disease mechanism (BAP1 tumor predisposition syndrome). NM_004656.4 is the MANE Select transcript. Under PMC6185798, a frameshift in a gene with confirmed germline LoF mechanism qualifies for PVS1 at full strength. Details ▾Hide ▴
Evidence considered
  • Frameshift variant creating PTC at codon 184 (NMD expected)
  • BAP1 loss-of-function is established germline disease mechanism per literature review (PMID:35051358
  • PMID:35348477
  • PMID:39842618)
  • NM_004656.4 is MANE Select transcript
  • No population LoF enrichment in exon 6 to warrant downgrade
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingThis variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the non-VCEP PM2 threshold of allele frequency below 0.1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 3 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant mutational hotspot in BAP1. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis negative for this residue
PP3 Per PMC6185798, splice prediction scores are not stacked with PVS1 for the same variant. REVEL and BayesDel are not applicable to this frameshift deletion. Although SpliceAI predicts acceptor loss (DS_AL=1.0, DS_AG=0.99), this overlaps with the PVS1 evidence of a null variant effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 (acceptor loss)
  • not independently scored due to PVS1 overlap
  • REVEL/BayesDel not applicable (not SNV)
Sources
spliceai ↗pvs1_generic_framework ↗
BP4 No in silico evidence supporting a benign effect. SpliceAI predicts acceptor loss (max delta 1.0). REVEL and BayesDel are not applicable to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 predicts damaging splice effect
  • not benign
  • REVEL/BayesDel not applicable (not SNV)
Sources
spliceai ↗

Not assessed · 14 · no assessment recorded

PS2 No de novo data available for this variant. No case reports with parental testing were identified. Details ▾Hide ▴
Still missing
  • No de novo observations available
PS3 No variant-specific functional studies identified. Two publications (PMID:18757409, PMID:21874000) discuss BAP1 tumor suppressor function at the gene level but neither mentions NM_004656.4:c.376_382del or the resulting protein change p.S126Dfs*59. Details ▾Hide ▴
Evidence considered
  • PMID:18757409 and PMID:21874000 reviewed
  • neither contains variant-specific functional data
Still missing
  • No variant-specific functional studies available
PS4 Variant is absent from ClinVar and no case reports with this specific variant were identified in the literature reviewed. Details ▾Hide ▴
Still missing
  • No case reports or ClinVar entries for this variant
PM6 No de novo observations reported for this variant. PM6 requires a confirmed de novo event in a patient without family history. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data
PP4 No patient phenotype data provided for this specific variant assessment. Details ▾Hide ▴
Still missing
  • Patient phenotype specificity not evaluated
PP5 Variant is absent from ClinVar; no expert panel classification available to support PP5. Details ▾Hide ▴
Still missing
  • No ClinVar entry from expert panel
BS2 No data on observation of this variant in healthy adults. Absence from gnomAD does not constitute BS2 evidence. Details ▾Hide ▴
Still missing
  • No healthy adult observation data
BS3 No variant-specific functional studies demonstrating a benign effect were identified. The two publications reviewed discuss BAP1 tumor suppressor function at gene level only. Details ▾Hide ▴
Evidence considered
  • PMID:18757409 and PMID:21874000 reviewed
  • neither contains variant-specific benign functional data
Still missing
  • No variant-specific benign functional data
BS4 No segregation data available for assessing lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data
BP2 No data on observation of this variant in trans with a known pathogenic variant in BAP1. Details ▾Hide ▴
Still missing
  • No in trans observation data
BP5 No data on an alternative molecular basis for disease in affected individuals carrying this variant. Details ▾Hide ▴
Still missing
  • No alternative molecular basis data
BP6 No reputable source has classified this variant as benign. Variant is absent from ClinVar. Details ▾Hide ▴
Still missing
  • No benign classification from any source
PS5 Variant is absent from ClinVar; no expert panel classification available. Details ▾Hide ▴
Still missing
  • No ClinVar entry for this variant
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid change via different nucleotide change. This is a 7bp frameshift deletion, not a nucleotide substitution at a known pathogenic missense site. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions or insertions in non-repeat regions. This variant is a 7bp frameshift deletion, which is assessed under PVS1 rather than PM4. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 evaluates a novel missense change at the same residue as a known pathogenic missense variant. This is a frameshift deletion, not a missense variant, and the residue-level comparator semantics are not applicable. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to genes where missense variants are a common disease mechanism. BAP1 disease is driven by loss-of-function variants, and HCI prior data is not available for this gene. Details ▾Hide ▴

No further detail was recorded.

BA1 N/ABA1 requires allele frequency above 1% in population databases. This variant is absent from gnomAD. Details ▾Hide ▴

No further detail was recorded.

BS1 N/ABS1 requires allele frequency above 0.3% in population databases. This variant is absent from gnomAD. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant itself is a truncating frameshift, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions in repetitive regions. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
BAP1
Transcript
NM_004656.4
Coding (HGVS c.)
NM_004656.4:c.376_382del
Protein (HGVS p.)
NP_004647.1:p.(Ser126AspfsTer59)
GRCh38
chr3:52407453 CCTTTGCT>C
GRCh37
chr3:52441469 CCTTTGCT>C

Gene diagram

Every interpreted variant in BAP1, mapped onto the exon structure of NM_004656.4. Select a row to find it on the plot.

BAP1NM_004656.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +7 bp
1.000
SpliceAI acceptor gainat +0 bp
0.990
SpliceAI donor lossat -353 bp
0.000
SpliceAI donor gainat +417 bp
0.010
Pangolin splice lossmagnitude shown
-0.940
Pangolin splice gain
0.880

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Per PMC6185798, splice prediction scores are not stacked with PVS1 for the same variant. REVEL and BayesDel are not applicable to this frameshift deletion. Although SpliceAI predicts acceptor loss (DS_AL=1.0, DS_AG=0.99), this overlaps with the PVS1 evidence of a null variant effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 (acceptor loss)
  • not independently scored due to PVS1 overlap
  • REVEL/BayesDel not applicable (not SNV)
Sources
spliceai ↗pvs1_generic_framework ↗
BP4 No in silico evidence supporting a benign effect. SpliceAI predicts acceptor loss (max delta 1.0). REVEL and BayesDel are not applicable to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 predicts damaging splice effect
  • not benign
  • REVEL/BayesDel not applicable (not SNV)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
    This paper demonstrates that BAP1 has tumor suppressor activity and that cancer-associated BAP1 mutations result in loss of deubiquitinating activity and nuclear localization. NM_004656.4:c.376_382del (p.S126Dfs*59) was not identified in the full text.
    Does not name this variant
    PMID 18757409 ↗
  • Germline BAP1 mutations predispose to malignant mesothelioma.
    This paper reports germline BAP1 mutations predisposing to malignant mesothelioma in two families, identifying truncating mutations and observing somatic BAP1 alterations in mesothelioma tumors. NM_004656.4:c.376_382del (p.S126Dfs*59) was not identified in the full text.
    Does not name this variant
    PMID 21874000 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 1.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.