About BAP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BAP1 c.86T>G, p.(Val29Gly)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
p.Val29Gly is located in the ubiquitin C-terminal hydrolase (UCH) domain of BAP1, a well-established critical functional domain. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating no benign variation at this residue. PMID:30517737 explicitly assigns PM1 to p.V29G in its ACMG assessment.
PM2Moderate
PM2 · moderate
Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes+genomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is below the PM2 threshold of <0.1% in all population databases examined.
PP3Supporting
PP3 · supporting
Multiple lines of computational evidence support a deleterious effect on the gene product. REVEL score is 0.77, exceeding the 0.5 and 0.75 thresholds used by many clinical laboratories. PMID:30517737 explicitly assigns PP3 to p.V29G. SpliceAI predicts no splice impact (max delta 0.03), which is not contradictory — this is a missense, not splice variant.
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: PM1 moderate, PM2 moderate, PP3 supporting; combination = 2 moderate + 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BAP1, a nuclear ubiquitin hydrolase, is frequently altered by mutation in various cancers.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 17 not met · 3 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004656.4:c.86T>G (p.Val29Gly) in BAP1 is a missense variant in exon 3, located within the ubiquitin C-terminal hydrolase (UCH) domain.
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength.
The variant resides in the UCH domain, a critical functional domain of BAP1 without evidence of benign variation at this residue, meeting PM1 at moderate strength as assigned by the Walpole et al. 2018 global cohort study.
Computational evidence supports a deleterious effect: REVEL score 0.77 exceeds commonly used thresholds, and Walpole et al. explicitly assigned PP3 to p.V29G, meeting PP3 at supporting strength.
A saturation genome editing study of BAP1 (PMID:38969833) was reviewed in full but did not include p.Val29Gly; the Ambry Genetics ClinVar PS3 functional signal citing this paper could not be validated.
No variant-specific functional studies, de novo observations, or segregation data sufficient to meet PS3, PS2, or PP1 were identified.
With two moderate criteria (PM1, PM2) and one supporting criterion (PP3) met, and no benign criteria met, this variant does not reach the likely pathogenic threshold (requires ≥3 moderate, or 2 moderate + 2 supporting) under the generic ACMG/AMP 2015 classification framework and is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM1 Moderatep.Val29Gly is located in the ubiquitin C-terminal hydrolase (UCH) domain of BAP1, a well-established critical functional domain. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating no benign variation at this residue. PMID:30517737 explicitly assigns PM1 to p.V29G in its ACMG assessment. Details ▾Hide ▴
Evidence considered
- PMID:30517737 line 255-259: 'all have PM1 and PP3.' UCH domain (amino acids 1-240) houses all nine missense variants with evidence of pathogenicity. Absent from all population databases.
Sources
PM2 ModerateAbsent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes+genomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is below the PM2 threshold of <0.1% in all population databases examined. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- gnomAD v4.1
- and gnomAD-Canada v1.0. AF = 0.0
- homozygotes = 0.
Sources
PP3 SupportingMultiple lines of computational evidence support a deleterious effect on the gene product. REVEL score is 0.77, exceeding the 0.5 and 0.75 thresholds used by many clinical laboratories. PMID:30517737 explicitly assigns PP3 to p.V29G. SpliceAI predicts no splice impact (max delta 0.03), which is not contradictory — this is a missense, not splice variant. Details ▾Hide ▴
Evidence considered
- REVEL score 0.77 (deleterious). SpliceAI max delta 0.03 (no splice impact
- not contradictory for missense). PMID:30517737 line 256: 'all have PM1 and PP3.' BayesDel 0.315 is below typical damaging threshold but does not outweigh the REVEL score and expert assignment.
Sources
Not met · 17 · evaluated, threshold not reached
PS3 Well-established functional studies supporting a damaging effect were not identified. The Ambry Genetics ClinVar submission (SCV006197225) cited PMID:38969833 for functional evidence, but full-text review confirmed that NM_004656.4:c.86T>G (p.Val29Gly) is not mentioned in that saturation genome editing study. No other variant-specific functional assays were found. Details ▾Hide ▴
Evidence considered
- PMID:38969833 reviewed in full: saturation genome editing of BAP1 does not include p.Val29G in the reported data or text. Ambry ClinVar functional PS3 signal could not be validated.
Still missing
- No variant-specific functional assay (e.g.
- deubiquitinase activity
- cell survival) has been performed for p.Val29Gly. The SGE study in PMID:38969833 may include V29G in supplementary data not available in the extracted full text
- review of supplementary tables is recommended.
Sources
PS4 PS4 requires a statistically enriched observation of the variant in affected individuals versus controls. PMID:30517737 includes p.V29G in a global BAP1-TPDS cohort but does not provide sufficient case counts or control comparison data to support PS4. The variant was listed among six missense variants with 'some evidence of pathogenicity' but insufficient to reach likely pathogenic threshold. Details ▾Hide ▴
Evidence considered
- PMID:30517737: p.V29G included in global BAP1 germline cohort
- variant grouped among six with PM1 and PP3 but not reaching LP. Specific case counts not extractable from available text (detailed in Supplementary Table 2
- not available).
Still missing
- Supplementary Table 2 of PMID:30517737 unavailable
- may contain individual-level phenotype data for PS4 assessment.
Sources
PP1 PP1 requires co-segregation with disease in multiple affected family members. PMID:30517737 states that the six variants including p.V29G have 'some have varying levels of PP1 and PP4,' but does not confirm whether p.V29G specifically meets PP1. Without the Supplementary Table 2 data, co-segregation evidence cannot be attributed to this specific variant. Details ▾Hide ▴
Evidence considered
- PMID:30517737 line 257-258: 'some have varying levels of PP1 and PP4' — ambiguous whether V29G specifically has PP1. Supplementary Table 2 unavailable.
Still missing
- Supplementary Table 2 of PMID:30517737 may contain family-specific segregation data for p.V29G.
Sources
PP2 PP2 applies to genes with a low rate of benign missense variation where missense variants are a common disease mechanism. For BAP1, the primary disease mechanism is loss of function (nonsense, frameshift, splice). Missense variants account for a small proportion of known pathogenic BAP1 variants, and >98% of observed missense variants are classified as VUS. PP2 is not met. Details ▾Hide ▴
Evidence considered
- BAP1 disease is primarily driven by null variants. Most missense variants are VUS.
PP4 PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease. PMID:30517737 mentions 'some have varying levels of PP4' among the six variants including p.V29G, but without specific patient-level phenotype data for this variant, PP4 cannot be independently confirmed. Details ▾Hide ▴
Evidence considered
- PMID:30517737 line 257-258: ambiguous whether V29G specifically meets PP4. No patient-level phenotype data available in extracted text.
Still missing
- Supplementary Table 2 of PMID:30517737 may contain proband phenotype for p.V29G.
Sources
PP5 No reputable source has definitively classified this variant as pathogenic. ClinVar contains conflicting classifications: two clinical laboratories report Uncertain significance, and one reports Likely pathogenic (Ambry Genetics), but the Ambry classification cited functional evidence (PMID:38969833) that does not contain this variant. No expert panel review is available. Details ▾Hide ▴
Evidence considered
- ClinVar 539911: 2 VUS
- 1 LP (Ambry). No expert panel. Ambry LP classification cites unverifiable PMID:38969833 functional evidence.
Sources
BA1 BA1 requires allele frequency >1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Absent from all population databases.
Sources
BS1 BS1 requires allele frequency >0.3% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Absent from all population databases.
Sources
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No such evidence is available for this variant. Details ▾Hide ▴
Evidence considered
- No evidence of healthy adult carriers.
BS3 BS3 requires well-established functional studies showing no damaging effect. No functional studies of p.Val29Gly demonstrating a benign effect were identified. Details ▾Hide ▴
Evidence considered
- No benign functional data available.
Still missing
- Functional studies for p.Val29Gly have not been performed or reported.
BS4 BS4 requires lack of segregation in affected family members. No segregation data demonstrating absence of co-segregation were identified. Details ▾Hide ▴
Evidence considered
- No non-segregation data available.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. Although BAP1-TPDS is predominantly caused by null variants, pathogenic missense variants in BAP1 are well-documented, including three reaching likely pathogenic classification in PMID:30517737, and missense variants in BAP1 cause Kury-Isidor syndrome (PMID:35051358). Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- PMID:30517737 identified three likely pathogenic missense variants (p.H94R
- p.L100P
- p.Y173C). BAP1 missense variants also cause Kury-Isidor neurodevelopmental syndrome.
Sources
BP2 BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such evidence is available. Details ▾Hide ▴
Evidence considered
- No trans/cis phase data available.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.77 supports a deleterious effect, and SpliceAI max delta of 0.03 is not informative for a missense variant. BayesDel 0.315 is below typical damaging thresholds but does not constitute 'multiple lines' of benign computational evidence. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.77 (deleterious). BayesDel 0.315 (borderline neutral). SpliceAI max delta 0.03 (no splice impact
- not applicable to missense). Computational evidence is not uniformly benign.
Sources
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such evidence was identified. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis identified.
BP6 BP6 requires a reputable source to report the variant as benign. ClinVar classification for this variant is Uncertain significance (2 submitters) and Likely pathogenic (1 submitter). No submitter has classified this variant as benign or likely benign. Details ▾Hide ▴
PS5 No reputable source has definitively classified this variant as pathogenic with evidence available for independent evaluation. ClinVar shows conflicting classifications: two submitters report Uncertain significance; one submitter (Ambry Genetics) reports Likely pathogenic, but the cited functional evidence (PMID:38969833) does not mention this variant. This does not meet PS5 threshold. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 539911: 2 submitters VUS
- 1 submitter LP. No expert panel review. Ambry LP classification cited unverifiable functional evidence.
Sources
Not assessed · 3 · no assessment recorded
PS1 PS1 requires a different nucleotide change at the same codon producing the same missense change (p.Val29Gly) with established pathogenicity. No such comparator variant was identified in the evidence packet, ClinVar records, or publications. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change yielding p.Val29Gly with established pathogenic classification was identified.
Still missing
- No systematic search for alternate nucleotide variants at codon 29 producing Val29Gly.
PS2 PS2 requires de novo confirmation with both maternity and paternity confirmed. No de novo testing data for this variant was available in the evidence packet, ClinVar submissions, or reviewed literature. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- Parental testing not available.
PM6 PM6 requires a de novo observation with maternity and paternity confirmed. No de novo evidence for NM_004656.4:c.86T>G was identified in ClinVar submissions, publications, or the evidence packet. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- Parental testing data not available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.86T>G, p.Val29Gly) does not fall into PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework is not applicable to this class of variant. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 29
- variant_bucket 'other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to confirm classic same-residue PM5 semantics safely; no candidate comparator variants at codon 29 with an established pathogenic classification were identified. The automated pm5_candidates harvest returned zero candidates. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: found=false
- zero same_residue_candidates
- zero candidates total. Recommendation level: not_applicable.
Still missing
- Manual ClinVar search for other pathogenic variants at codon 29 could be considered.
Sources
pm5_candidates
BP3 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous (silent) variants. NM_004656.4:c.86T>G is a missense variant producing p.Val29Gly. Details ▾Hide ▴
Evidence considered
- Missense variant c.86T>G
- protein change p.Val29Gly — not synonymous.
Identifiers
- Gene
- BAP1
- Transcript
- NM_004656.4
- Coding (HGVS c.)
- NM_004656.4:c.86T>G
- Protein (HGVS p.)
- NP_004647.1:p.(Val29Gly)
- GRCh38
- chr3:52409590 A>C
- GRCh37
- chr3:52443606 A>C
- ClinVar
- 539911
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…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BAP1
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.770
- BayesDel
- 0.315
How the predictions were used
PP3 SupportingMultiple lines of computational evidence support a deleterious effect on the gene product. REVEL score is 0.77, exceeding the 0.5 and 0.75 thresholds used by many clinical laboratories. PMID:30517737 explicitly assigns PP3 to p.V29G. SpliceAI predicts no splice impact (max delta 0.03), which is not contradictory — this is a missense, not splice variant. Details ▾Hide ▴
Evidence considered
- REVEL score 0.77 (deleterious). SpliceAI max delta 0.03 (no splice impact
- not contradictory for missense). PMID:30517737 line 256: 'all have PM1 and PP3.' BayesDel 0.315 is below typical damaging threshold but does not outweigh the REVEL score and expert assignment.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.77 supports a deleterious effect, and SpliceAI max delta of 0.03 is not informative for a missense variant. BayesDel 0.315 is below typical damaging thresholds but does not constitute 'multiple lines' of benign computational evidence. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.77 (deleterious). BayesDel 0.315 (borderline neutral). SpliceAI max delta 0.03 (no splice impact
- not applicable to missense). Computational evidence is not uniformly benign.
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants. NM_004656.4:c.86T>G is a missense variant producing p.Val29Gly. Details ▾Hide ▴
Evidence considered
- Missense variant c.86T>G
- protein change p.Val29Gly — not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.77. BayesDel score = 0.315276.
5 paper records listed. 1 cited in the classification.
Cited in the classification
-
PMID 30517737 ↗Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.Walpole S et al. · 2018 Dec 1p.V29G is identified among six missense variants with some evidence of pathogenicity. All six had PM1 and PP3; some also had varying levels of PP1 and PP4, though none reached the likely pathogenic ACMG/AMP threshold. All nine missense variants identified in this study with evidence of pathogenicity occur in the UCH domain.→ PM1 → PP3 Names this variant
Source detail
We also identified an additional six variants (p.L14H, p.V29G, p.D67G, p.N78S, p.L180P, p.W202R) that have some evidence of pathogenicity (ie, all have PM1 and PP3 and some have varying levels of PP1 and PP4) but do not reach the likely pathogenic ACMG threshold
Location Results, paragraphs on missense variant classification (lines 248-259) and Discussion (lines 808-818)
Other recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a framework document and does not discuss any specific variant, including NM_004656.4:c.86T>G.Does not name this variant
-
PMID 38969833 ↗Saturation genome editing of BAP1 functionally classifies somatic and germline variants.Waters AJ et al. · 2024Saturation genome editing study of BAP1 experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal function. NM_004656.4:c.86T>G (p.Val29Gly) was not identified anywhere in the full text.Does not name this variant
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline for cancer predisposition referral indications. Discusses referral criteria for hereditary cancer syndromes at the gene level. NM_004656.4:c.86T>G is not mentioned in this guideline document.Does not name this variant
-
PMID 27748099 ↗BAP1 Tumor Predisposition Syndrome.Adam MP et al. · 1993GeneReviews entry for BAP1 Tumor Predisposition Syndrome. Full text was not available for review; only a screenshot image was present in the case directory. Without full-text access, variant-specific mention could not be confirmed or excluded.Does not name this variant
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 0.030
Open source ↗
ClinVar
2 Uncertain significance · 1 Likely pathogenic
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/539911/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-52443606-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-52409590-A-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-52409590-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004656.4%3Ac.86T%…
- OncoKB ↗www.oncokb.org/gene/BAP1/V29G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BAP1+c.86T%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
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 has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 539911)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.77. BayesDel score = 0.315276.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BAP1, a nuclear ubiquitin hydrolase, is frequently altered by mutation in various cancers.
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.