GeneBe

BRCC3

protein-coding

BRCA1/BRCA2-containing complex subunit 3, the group of BRCA1 A complex|BRISC complex|JAMM/MPN+ metallopeptidase family

Gene summary

This gene encodes a subunit of the BRCA1-BRCA2-containing complex (BRCC), which is an E3 ubiquitin ligase. This complex plays a role in the DNA damage response, where it is responsible for the stable accumulation of BRCA1 at DNA break sites. The component encoded by this gene can specifically cleave Lys 63-linked polyubiquitin chains, and it regulates the abundance of these polyubiquitin chains in chromatin. The loss of this gene results in abnormal angiogenesis and is associated with syndromic moyamoya, a cerebrovascular angiopathy. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 5. [provided by RefSeq, Jun 2011]

Previous symbols:
  • CXorf53

MANE transcript

NM_001018055.3

Inheritance

XL, AD

ClinVar variants

U:53B:2

Top phenotype

Hereditary cancer-predisposing syndrome

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chrX:155,071,420-155,123,077

External References & Databases

Ensembl (ENSG00000185515)NCBI Gene (79184)OMIM (300617)HGNC:24185GenCCUniProt (P46736)AlphaFoldClinVar (BRCC3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~51.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Moyamoya diseaseLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0016820

Submitter: Ambry Genetics

Moyamoya diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016820

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BRCC3 variants in ClinVar

3 Conditions Cataloged
Hereditary cancer-predisposing syndromeTotal: 8
not providedTotal: 6
not specifiedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001018055.3. 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
11
clinvar
2
clinvar
 13
missense
26
clinvar
 26
nonsense
3
clinvar
 3
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
13
clinvar
 13
Total00532055
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001018055.3RefSeqNP_001018065.110MANE Select
ENST00000330045.12EnsemblENSP00000328641.710MANE Select
NM_001242640.2RefSeqNP_001229569.110Standard
NM_024332.4RefSeqNP_077308.111Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
brcc3Danio rerio

Structure: vascular sprouts

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • NOD-like receptor signaling pathway - Homo sapiens (human)
  • Homologous recombination - Homo sapiens (human)
  • HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
  • DNA Repair
  • Nonhomologous End-Joining (NHEJ)

Biological Process

  • DNA repair
  • double-strand break repair
  • double-strand break repair via nonhomologous end joining
  • cell cycle
  • response to X-ray

Molecular Function

  • thiol-dependent ubiquitin-specific protease activity
  • protein binding
  • metallopeptidase activity
  • enzyme regulator activity
  • polyubiquitin modification-dependent protein binding

Cellular Component

  • ubiquitin ligase complex
  • nuclear ubiquitin ligase complex
  • spindle pole
  • nucleus
  • nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000369462
Coding exons
11
Length
51655
Individuals with no LoFs
124646
Homozygous LoFs
2
Heterozygous LoFs
4
Defined
124652
p
0.0000241
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.67321110.2880.000008272067
Missense (PolyPhen)239.0880.051167821
Synonymous0.6163641.00.8780.00000309579
Loss of Function2.08614.60.4120.00000116236

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000640.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Metalloprotease that specifically cleaves 'Lys-63'- linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double- strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). {ECO:0000269|PubMed:14636569, ECO:0000269|PubMed:16707425, ECO:0000269|PubMed:17525341, ECO:0000269|PubMed:19202061, ECO:0000269|PubMed:19214193, ECO:0000269|PubMed:19261746, ECO:0000269|PubMed:19261748, ECO:0000269|PubMed:19261749, ECO:0000269|PubMed:20656690, ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:26195665, ECO:0000269|PubMed:26344097}.;

Recessive Scores

pRec
0.194

Intolerance Scores

LoFtool
0.521
RVIS EVS
0.21
RVIS percentile EVS
67.72

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.237

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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