SMARCA4

protein-coding

SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4, the group of Bromodomain containing|BAF complex|GBAF complex|PBAF complex

Gene summary

The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

Previous symbols:

SNF2L4

MANE transcript

NM_003072.5

Inheritance

AR, AD

ClinVar variants

P:376U:2688B:1995

Top phenotype

Rhabdoid tumor predisposition syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.01

Max pathogenic AF

—

Genomic locus

chr19:10,960,932-11,079,426

External References & Databases

Ensembl (ENSG00000127616)

Transcript & Mutation Effects

hg38 • Region Span ~118.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

uterine corpus sarcomaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005210

Submitter: Genomics England PanelApp

hereditary nonpolyposis colon cancerLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018630

Submitter: ClinGen

rhabdoid tumor predisposition syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013224

Submitter: Ambry Genetics

intellectual disability, autosomal dominant 16STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013821

Submitter: Ambry Genetics

intellectual disability, autosomal dominant 16STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013821

Submitter: Labcorp Genetics (formerly Invitae)

Coffin-Siris syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: ClinGen

*SMARCA4* was first reported in relation to autosomal dominant Coffin-Siris syndrome (CSS) in 2012 (Tsurusaki et al., PMID: 22426308). CSS is a syndromic form of cognitive and developmental disability most commonly associated with fifth finger hypoplasia and distinctive facial dysmorphisms, including a wide mouth with thick, everted lips, thick eyebrows, and a broad nasal bridge, consistent with facial coarseness. Congenital anomalies of the brain, kidney, and heart have been described but are less consistent across patients. Approximately 35% of all CSS patients have congenital heart disease, typically including ventricular septal defect, atrial septal defect, and tetralogy of Fallot (PMIDs: 23556151, 25298701, 31160358). Pathogenic variants in several genes encoding components of the BAF chromatin remodeling complex, including *ARID1A*, *ARID1B*, *ARID2*, *SMARCA4*, *SMARCB1*, *SMARCC2*, *SMARCD1*, *SMARCE1*, and *DPF2*, cause CSS (PMIDs: 25168959, 31530938). Heterozygous *SMARCA4* pathogenic variants cause ~12% of CSS cases (PMID: 30123105). Twenty-three unique *de novo* missense or in-frame variants (PMIDs: 22426308, 30792901, 31530938, 32686290, 38177409) and three frameshift or nonsense variants (PMIDs: 28608987, 32686290) that have been reported in 26 probands with CSS have been included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most variants occur *de novo*. Almost all pathogenic missense variants reported in CSS cases are localized in the middle of the gene (within or near the HAS, DEXDc, and HELICc functional domains) and are expected to exert a dominant-negative or gain-of-function effect. Experimental evidence supporting this gene-disease relationship includes the biochemical function of *SMARCA4*, protein interaction with *ADNP* and other BAF protein complex subunits, and mouse models recapitulating some of the neurological and cardiovascular phenotypes of CSS (PMIDs: 17878164, 23319608, 23698369, 26459759). SMARCA4 is involved in chromatin remodeling and transcriptional activation. Although pathogenic variants have been shown to alter transcriptional activation of development regulator genes (PMID: 23319608), the mechanism by which *SMARCA4* pathogenic variants cause CSS is not clear. In summary, there is definitive evidence supporting the relationship between *SMARCA4* and autosomal dominant Coffin-Siris syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was initially approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel (GCEP) on June 17, 2020 (SOP Version 7). This gene-disease relationship was recurated by the ClinGen Congenital Heart Disease GCEP on June 9, 2025 with an updated SOP Version 11 to include more probands in the curation, however the classification remained the same (PMIDs: 31530938, 32686290, 38177409).

Coffin-Siris syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: Illumina

familial rhabdoid tumorSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016473

Submitter: Orphanet

Coffin-Siris syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: Orphanet

rhabdoid tumor predisposition syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013224

Submitter: G2P

otosclerosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005349

Submitter: PanelApp Australia

rhabdoid tumor predisposition syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013224

Submitter: ClinGen

There has been sufficient amount of evidence published associating the SMARCA4 gene with rhabdoid tumor predisposition syndrome 2 (RTPS) since the gene-disease relationship was first proposed by Schneppenheim et al. (2010). Plenty of case level studies have been performed with RTPS patients that have variants in the SMARCA4 gene. SMARCB1, another subunit of the SWI/SNF chromatin remodeling complexes, also cause RTPS. Tumor cells from patients lacked SMARCA4 immunoreactivity and depletion of SMARCA4 increase cell growth. Reintroduction of SMARCA4 in SMARCA4-null H1299 cells resulted in a dose-dependent suppression of cell growth. SMARCA4 heterozygote mice are predisposed to exencephaly and tumors. All of these evidences suggest a definitive relationship between the SMARCA4 gene and rhabdoid tumor predisposition syndrome 2 (RTPS).

intellectual disability, autosomal dominant 16DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013821

Submitter: G2P

rhabdoid tumor predisposition syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013224

Submitter: Genomics England PanelApp

rhabdoid tumor predisposition syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013224

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Rhabdoid tumor predisposition syndrome 2AD

Manifestation: Cardiovascular; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Genitourinary

Intervention: Oncologic

Rationale: Individuals may be at high risk for a variety of undifferentiated tumor types, and surveillance and early diagnosis/treatment may be beneficial

Refs: 20137775; 22426308; 23775540; 24658001; 24658002; 24752781

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMARCA4 variants in ClinVar

40 Conditions Cataloged

Rhabdoid tumor predisposition syndrome 2Total: 5200

Hereditary cancer-predisposing syndromeTotal: 3889

not providedTotal: 954

Intellectual disability, autosomal dominant 16Total: 697

SMARCA4-related disorderTotal: 351

not specifiedTotal: 321

Coffin-Siris syndromeTotal: 69

Otosclerosis 12Total: 53

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003072.5. 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			20 clinvar	1806 clinvar	9 clinvar	1835
missense	16 clinvar	83 clinvar	2600 clinvar	177 clinvar	1 clinvar	2877
nonsense	73 clinvar	13 clinvar	15 clinvar			101
start loss			2 clinvar			2
frameshift	103 clinvar	17 clinvar	16 clinvar			136
splice donor/acceptor (+/-2bp)	4 clinvar	67 clinvar	35 clinvar	2 clinvar		108
Total	196	180	2688	1985	10	5059

Highest pathogenic variant AF is 0.0000065719432

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 177 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003072.5	RefSeq	NP_003063.2	34	MANE Select
ENST00000344626.10	Ensembl	ENSP00000343896.4	34	MANE Select
NM_001128844.3	RefSeq	NP_001122316.1	34	Standard
NM_001128845.2	RefSeq	NP_001122317.1	33	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
smarca4a	Danio rerio	Structure: cardiac muscle cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

smarca4a

Danio rerio

Structure: cardiac muscle cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
Hepatocellular carcinoma - Homo sapiens (human)
Androgen Receptor Network in Prostate Cancer
Preimplantation Embryo
Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex

Biological Process

negative regulation of transcription by RNA polymerase II
RNA polymerase I preinitiation complex assembly
neural retina development
chromatin organization
nucleosome disassembly

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
RNA polymerase I CORE element sequence-specific DNA binding
p53 binding
transcription coactivator activity

Cellular Component

nuclear chromatin
extracellular space
nucleus
nucleoplasm
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000429416
Coding exons: 34
Length: 104474
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125748
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	6.85	423	1.05e+3	0.404	0.0000773	10728
Missense (PolyPhen)		120	453.37	0.26468		4695
Synonymous	-2.00	511	457	1.12	0.0000385	3212
Loss of Function	8.48	1	85.8	0.0117	0.00000502	944

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating the calcium-dependent release of a repressor complex and the recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by SMARCA4- dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST- dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves the release of HDAC1 and recruitment of CREBBP. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development, a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues (By similarity). Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial- mesenchymal transition (EMT) by ZEB1. Binds via DLX1 to enhancers located in the intergenic region between DLX5 and DLX6 and this binding is stabilized by the long non-coding RNA (lncRNA) Evf2 (By similarity). Binds to RNA in a promiscuous manner (By similarity). Binding to RNAs including lncRNA Evf2 leads to inhibition of SMARCA4 ATPase and chromatin remodeling activities (By similarity). {ECO:0000250|UniProtKB:Q3TKT4, ECO:0000269|PubMed:19571879, ECO:0000269|PubMed:20418909, ECO:0000269|PubMed:29374058, ECO:0000303|PubMed:22952240, ECO:0000303|PubMed:26601204}.;
Disease: DISEASE: Coffin-Siris syndrome 4 (CSS4) [MIM:614609]: A form of Coffin-Siris syndrome, a congenital multiple malformation syndrome with broad phenotypic and genetic variability. Cardinal features are intellectual disability, coarse facial features, hypertrichosis, and hypoplastic or absent fifth digit nails or phalanges. Additional features include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Sucking/feeding difficulties, poor growth, ophthalmologic abnormalities, hearing impairment, and spinal anomalies are common findings. Both autosomal dominant and autosomal recessive inheritance patterns have been reported. {ECO:0000269|PubMed:22426308}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.506

Intolerance Scores

LoFtool: 0.000689
RVIS EVS: -2.85
RVIS percentile EVS: 0.6

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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