BRD4
protein-codingbromodomain containing 4, the group of Bromodomain and extra-terminal domain family|Bromodomain containing
Gene summary
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human RING3 protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines an upper respiratory tract carcinoma in young people. Two alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~97.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0957921
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0957921
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000508
Submitter: ClinGen
The *BRD4* gene encodes a member of the bromodomain and extra-terminal domain (BET) family of nuclear proteins. It binds to lysine-acetylated histones, non-histone proteins, DNA and RNA, and plays a role in transcription, replication, and DNA repair. *BRD4* was first reported in relation to autosomal dominant syndromic intellectual disability in 2018 (Olley et al., PMID: 29379197). The clinical features include global developmental delay, variable intellectual disability, microcephaly, and dysmorphic facial features (PMIDs: 29379197, 35470444). Some individuals are reported to have a Cornelia de Lange syndrome–like appearance (PMID: 29379197). Ten variants (frameshift, nonsense, missense, intragenic deletion) that have been reported in 12 probands in five publications (PMIDs: 29379197, 31911672, 31981491, 33057194, 35470444) are included in this curation. Variants were *de novo* in all instances in which parental DNA was available. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Multigenic deletions encompassing the *BRD4* gene have been reported in individuals with intellectual disability and congenital anomalies, some of whom exhibit a Cornelia de Lange syndrome–like phenotype (PMIDs: 29379197, 30055032, 30302754, 35470444). The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by a *Brd4*-deficient mouse model (PMID: 11997514) and protein interactions with NIPBL, the major disease gene for Cornelia de Lange syndrome, and with BICRA and CHD4, also involved in syndromic intellectual disability. In summary, there is definitive evidence supporting the relationship between*BRD4* and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 20, 2022. It was reevaluated on August 8, 2025 (SOP Version 11). Although new cases (PMID: 35470444) were added, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0019042
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016033
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BRD4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001379291.1. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 280 | 19 | 305 | ||
| missense | 3 | 376 | 32 | 6 | 417 | |
| nonsense | 2 | 2 | 1 | 5 | ||
| start loss | 1 | 1 | ||||
| frameshift | 8 | 12 | 3 | 23 | ||
| splice donor/acceptor (+/-2bp) | 3 | 2 | 7 | 12 | ||
| Total | 13 | 19 | 394 | 312 | 25 | 763 |
Highest pathogenic variant AF is 0.00008557736
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001366220.1 | 19 | MANE Select | |
| Ensembl | ENSP00000506350.1 | 19 | MANE Select | |
| RefSeq | NP_001317313.1 | 11 | Standard | |
| RefSeq | NP_001366221.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| brd4 | Danio rerio | Structure: thrombocyte Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chemical Compounds to monitor Proteins
Biological Process
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- chromatin organization
- protein phosphorylation
- cellular response to DNA damage stimulus
- positive regulation of G2/M transition of mitotic cell cycle
Molecular Function
- p53 binding
- chromatin binding
- protein binding
- RNA polymerase II CTD heptapeptide repeat kinase activity
- enzyme binding
Cellular Component
- condensed nuclear chromosome
- nucleus
- nucleoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000263377
- Coding exons
- 19
- Length
- 95710
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125744
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.59 | 519 | 805 | 0.644 | 0.0000505 | 8836 |
| Missense (PolyPhen) | 8 | 14.834 | 0.53929 | 142 | ||
| Synonymous | -3.62 | 426 | 341 | 1.25 | 0.0000244 | 2678 |
| Loss of Function | 7.27 | 0 | 61.5 | 0.00 | 0.00000319 | 689 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P- TEFb complex and recruiting it to promoters: BRD4 is required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P- TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters. {ECO:0000269|PubMed:22509028}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. {ECO:0000269|PubMed:11733348, ECO:0000269|PubMed:12543779}.;
Recessive Scores
- pRec
- 0.187
Intolerance Scores
- LoFtool
- 0.363
- RVIS EVS
- -1.48
- RVIS percentile EVS
- 3.69
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.963
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |