BRWD3

protein-coding

bromodomain and WD repeat domain containing 3, the group of WD repeat domain containing|Bromodomain containing

Gene summary

The protein encoded by this gene contains a bromodomain and several WD repeats. It is thought to have a chromatin-modifying function, and may thus play a role in transcription. Mutations in this gene are associated with a spectrum of cognitive disabilities and X-linked macrocephaly. This gene is also associated with translocations in patients with B-cell chronic lymphocytic leukemia. [provided by RefSeq, Jul 2017]

MANE transcript

NM_153252.5

Inheritance

AD, XL

ClinVar variants

P:82U:671B:195

Top phenotype

Intellectual developmental disorder, X-linked 93

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chrX:80,669,503-80,809,877

External References & Databases

Ensembl (ENSG00000165288)

Transcript & Mutation Effects

hg38 • Region Span ~140.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

self-limited epilepsy with centrotemporal spikesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007295

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 93MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010393

Submitter: Ambry Genetics

infantile spasmsLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018097

Submitter: Ambry Genetics

X-linked syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0020119

Submitter: ClinGen

*BRWD3* is located on chromosome Xq21.1 and encodes a bromodomain‐ and WD40 repeat–containing protein involved in the regulation of chromatin dynamics, cytoskeletal organization, and intracellular signaling. *BRWD3* was first reported in relation to X-linked syndromic intellectual disability in 2007 (Field et al., PMID: 17668385). Affected males exhibit developmental delay, intellectual disability, speech delay, macrocephaly, overgrowth, and variable dysmorphic features. Some individuals also exhibit obesity or overweight, behavioral disturbances (including autism and ADHD) or epilepsy. Female carriers are typically unaffected but some exhibit mild cognitive impairment. Ten variants (5 nonsense, 3 frameshift, 1 splice, and 1 missense) that have been reported in ten probands in three publications (PMIDs: 17668385, 24462886, 28475857) are included in this curation. The missense variant has no functional evidence of pathogenicity and was given a score of 0. When segregation information was available, the variants were inherited from unaffected mothers. In several cases, the variants were shown to segregate with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Emerging experimental evidence (primarily studies in Drosophila) also supports this gene-disease relationship. In summary, there is definitive evidence supporting the relationship between *BRWD3* and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 18, 2018 (SOP Version 5). As of August 2026, this record underwent administrative updates to update scoring to be consistent with SOP Version 12. No new evidence was added.

intellectual developmental disorder, X-linked 93STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010393

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 93DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010393

Submitter: G2P

intellectual developmental disorder, X-linked 93STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010393

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 93XL

Manifestation: Craniofacial; Genitourinary; 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

Refs: 7943039; 17668385; 19377476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BRWD3 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 646

Inborn genetic diseasesTotal: 144

Intellectual disability, X-linked 93Total: 119

not specifiedTotal: 69

BRWD3-related disorderTotal: 35

Intellectual disabilityTotal: 5

Neurodevelopmental disorderTotal: 1

History of neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153252.5. 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			59 clinvar	133 clinvar	12 clinvar	204
missense	3 clinvar	6 clinvar	532 clinvar	44 clinvar	6 clinvar	591
nonsense	18 clinvar	16 clinvar	22 clinvar			56
start loss		1 clinvar				1
frameshift	14 clinvar	12 clinvar	3 clinvar			29
splice donor/acceptor (+/-2bp)	3 clinvar	9 clinvar	55 clinvar			67
Total	38	44	671	177	18	948

Highest pathogenic variant AF is 0.0000036462982

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153252.5	RefSeq	NP_694984.5	41	MANE Select
ENST00000373275.5	Ensembl	ENSP00000362372.4	41	MANE Select
NM_001441339.1	RefSeq	NP_001428268.1	40	Standard
ENST00001110106.1	Ensembl	ENSP00000779911.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
cytoskeleton organization
regulation of cell shape

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373275
Coding exons: 41
Length: 138835
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125729
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.27	369	683	0.540	0.0000516	11844
Missense (PolyPhen)		70	193.72	0.36134		3392
Synonymous	-0.904	242	225	1.08	0.0000161	3374
Loss of Function	7.83	2	75.4	0.0265	0.00000587	1253

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000037	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000088	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape. {ECO:0000269|PubMed:21834987}.;
Disease: DISEASE: Note=A chromosomal aberration involving BRWD3 can be found in patients with B-cell chronic lymphocytic leukemia (B- CLL). Translocation t(X;11)(q21;q23) with ARHGAP20 does not result in fusion transcripts but disrupts both genes.; DISEASE: Mental retardation, X-linked 93 (MRX93) [MIM:300659]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX93 is associated with macrocephaly. {ECO:0000269|PubMed:17668385}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0991

Intolerance Scores

LoFtool: 0.0934
RVIS EVS: -0.49
RVIS percentile EVS: 22.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.694

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium