GeneBe

BAP1

protein-coding

BRCA1 associated protein 1, the group of Ubiquitin C-terminal hydrolases

Gene summary

This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

MANE transcript

NM_004656.4

Inheritance

AD

ClinVar variants

P:472U:1333B:1075

Top phenotype

Tumor predisposition syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr3:52,401,008-52,410,008

External References & Databases

Ensembl (ENSG00000163930)NCBI Gene (8314)OMIM (603089)HGNC:950GenCCUniProt (Q92560)AlphaFoldClinVar (BAP1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~9.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

BAP1-related tumor predisposition syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: Genomics England PanelApp

BAP1-related tumor predisposition syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: Orphanet

BAP1-related tumor predisposition syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: Ambry Genetics

BAP1-related tumor predisposition syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: ClinGen

There is abundant published evidence associating the BAP1 gene with BAP1-related tumor predisposition syndrome since the gene-disease relationship was first proposed by Testa et al. (2011). Multiple case level studies have been performed with patients that have variants in the BAP1 gene. Immunohistochemistry on mesotheliomas from multiple families revealed lack of BAP1 nuclear expression. BAP1+/− mice develop more malignant mesotheliomas and spontaneous tumor development was found in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. Re-expression of BAP1 in BAP1-deficient mesothelioma cells markedly decreased colony-forming ability. All of these types of evidence are consistent with a definitive relationship between the BAP1 gene and BAP1-related tumor predisposition syndrome.

Kury-Isidor syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859230

Submitter: G2P

renal cell carcinomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005086

Submitter: Genomics England PanelApp

BAP1-related tumor predisposition syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: Ambry Genetics

BAP1-related tumor predisposition syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: G2P

Kury-Isidor syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859230

Submitter: Ambry Genetics

BAP1-related tumor predisposition syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013692

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Tumor predisposition syndrome 1AD

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic

Intervention: Dermatologic; Oncologic

Rationale: Awareness of oncologic risk may allow surveillance for and early treatment of a variety of malignancies (including uveal and cutaneous melanomas, mesothelioma, and several other types of cancer), which may reduce morbidity and mortality

Refs: 21941004; 21874000 21874003; 23032617; 23341325; 35051358Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BAP1 variants in ClinVar

21 Conditions Cataloged
BAP1-related tumor predisposition syndromeTotal: 2552
Hereditary cancer-predisposing syndromeTotal: 2432
not providedTotal: 489
not specifiedTotal: 215
BAP1-related disorderTotal: 144
Kury-Isidor syndromeTotal: 60
Melanoma, uveal, susceptibility to, 2Total: 58
Neurodevelopmental disorderTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004656.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
7
clinvar
801
clinvar
30
clinvar
 841
missense
7
clinvar
43
clinvar
1295
clinvar
232
clinvar
11
clinvar
 1588
nonsense
66
clinvar
11
clinvar
1
clinvar
1
clinvar
 79
start loss
3
clinvar
3
clinvar
 6
frameshift
215
clinvar
24
clinvar
10
clinvar
 249
splice donor/acceptor (+/-2bp)
23
clinvar
74
clinvar
20
clinvar
 117
Total31515713331034412880

Highest pathogenic variant AF is 0.00006133442

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004656.4RefSeqNP_004647.117MANE Select
ENST00000460680.6EnsemblENSP00000417132.117MANE Select
NM_001410772.1RefSeqNP_001397701.117Standard
ENST00000296288.10EnsemblENSP00000296288.517Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
bap1Danio rerio

Structure: neuron

Quality: hyperplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Pathways in clear cell renal cell carcinoma
  • DNA Repair
  • DNA Double-Strand Break Repair
  • Post-translational protein modification
  • Metabolism of proteins

Biological Process

  • regulation of cell growth
  • cellular protein modification process
  • ubiquitin-dependent protein catabolic process
  • negative regulation of cell population proliferation
  • response to inorganic substance

Molecular Function

  • chromatin binding
  • thiol-dependent ubiquitin-specific protease activity
  • protein binding
  • peptidase activity
  • thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol
  • PR-DUB complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000460680
Coding exons
17
Length
9338
Individuals with no LoFs
125702
Homozygous LoFs
0
Heterozygous LoFs
44
Defined
125746
p
0.000175
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.642774320.6420.00002804739
Missense (PolyPhen)70167.80.417151809
Synonymous0.1791761790.9830.00001181469
Loss of Function4.68433.00.1210.00000164404

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000410.00040rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.000190.00018rare
South Asian0.000200.00020rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1. Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1). Does not deubiquitinate monoubiquitinated histone H2B. Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'- linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains. Deubiquitination of HCFC1 does not lead to increase stability of HCFC1. Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination. It however does not mediate deubiquitination of BRCA1 and BARD1. Able to mediate autodeubiquitination via intramolecular interactions to couteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration (PubMed:24703950). Acts as a tumor suppressor. {ECO:0000269|PubMed:12485996, ECO:0000269|PubMed:18757409, ECO:0000269|PubMed:19117993, ECO:0000269|PubMed:19188440, ECO:0000269|PubMed:19815555, ECO:0000269|PubMed:20436459, ECO:0000269|PubMed:24703950, ECO:0000269|PubMed:9528852}.;
Disease
DISEASE: Mesothelioma, malignant (MESOM) [MIM:156240]: An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle- shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. {ECO:0000269|PubMed:21642991, ECO:0000269|PubMed:21874000}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Tumor predisposition syndrome (TPDS) [MIM:614327]: A condition characterized by predisposition to develop a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, lung adenocarcinoma and meningioma. {ECO:0000269|PubMed:21874000, ECO:0000269|PubMed:21874003}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.106

Intolerance Scores

LoFtool
0.364
RVIS EVS
-0.98
RVIS percentile EVS
8.85

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
0.689

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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