SMARCA4

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

Basic information

Region (hg38): 19:10960931-11079426

Previous symbols: [ "SNF2L4" ]

Links

ENSG00000127616 ∙ NCBI:6597 ∙ OMIM:603254 ∙ HGNC:11100 ∙ Uniprot:P51532 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Coffin-Siris syndrome 1 (Definitive), mode of inheritance: AD
• rhabdoid tumor predisposition syndrome 2 (Definitive), mode of inheritance: AD
• uterine corpus sarcoma (Moderate), mode of inheritance: AR
• rhabdoid tumor predisposition syndrome 2 (Strong), mode of inheritance: AD
• Coffin-Siris syndrome (Supportive), mode of inheritance: AD
• familial rhabdoid tumor (Supportive), mode of inheritance: AD
• intellectual disability, autosomal dominant 16 (Strong), mode of inheritance: AD
• rhabdoid tumor predisposition syndrome 2 (Strong), mode of inheritance: AD
• Coffin-Siris syndrome (Definitive), mode of inheritance: AD
• intellectual disability, autosomal dominant 16 (Strong), mode of inheritance: AD
• rhabdoid tumor predisposition syndrome 2 (Strong), mode of inheritance: AD
• hereditary nonpolyposis colon cancer (Limited), mode of inheritance: AD
• Coffin-Siris syndrome (Definitive), mode of inheritance: AD
• rhabdoid tumor predisposition syndrome 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Rhabdoid tumor predisposition syndrome 2	AD	Oncologic	Individuals may be at high risk for a variety of undifferentiated tumor types, and surveillance and early diagnosis/treatment may be beneficial	Cardiovascular; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Genitourinary	20137775; 22426308; 23775540; 24658001; 24658002; 24752781

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMARCA4 gene.

• Rhabdoid tumor predisposition syndrome 2 (4095 variants)
• Hereditary cancer-predisposing syndrome (2616 variants)
• Intellectual disability, autosomal dominant 16 (644 variants)
• not provided (615 variants)
• not specified (158 variants)
• Coffin-Siris syndrome (94 variants)
• SMARCA4-related condition (39 variants)
• Rhabdoid tumor predisposition syndrome 2;Intellectual disability, autosomal dominant 16 (33 variants)
• Intellectual disability, autosomal dominant 16;Rhabdoid tumor predisposition syndrome 2 (16 variants)
• Inborn genetic diseases (13 variants)
• SMARCA4-related BAFopathy (11 variants)
• Global developmental delay (3 variants)
• Neurodevelopmental disorder (2 variants)
• Small cell carcinoma of the ovary, hypercalcemic type;Coffin-Siris syndrome (2 variants)
• Cleft palate (1 variants)
• Hereditary cancer (1 variants)
• Coffin-Siris syndrome 1 (1 variants)
• Ventricular septal defect;Single transverse palmar crease;Global developmental delay;Facial asymmetry;Strabismus (1 variants)
• Neuroblastoma (1 variants)
• Microcephaly (1 variants)
• Intellectual disability, autosomal dominant 16;Small cell carcinoma of the ovary, hypercalcemic type (1 variants)
• See cases (1 variants)
• Delayed speech and language development;Ventricular septal defect;Atrial septal defect (1 variants)
• Malignant tumor of breast (1 variants)
• Intellectual disability (1 variants)
• Cerebral palsy;Intellectual disability (1 variants)
• Seizure (1 variants)
• Diffuse midline glioma, H3 K27-altered (1 variants)
• bilateral breast cancer (1 variants)
• Hereditary cancer-predisposing syndrome;Childhood neoplasm (1 variants)
• intellectual deficiency;Obesity (1 variants)
• Medulloblastoma (1 variants)
• Neoplasm of ovary (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMARCA4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			13	1396	10	1419
missense	7	38	1858	12	1	1916
nonsense	50	10	7			67
start loss			1	1		2
frameshift	61	5	10			76
inframe indel	1	1	71	1		74
splice donor/acceptor (+/-2bp)	1	43	15	2	1	62
splice region			163	203	4	370
non coding			32	667	72	771
Total	120	97	2007	2079	84

Highest pathogenic variant AF is 0.00000657

Variants in SMARCA4

This is a list of pathogenic ClinVar variants found in the SMARCA4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-10961134-C-T		Coffin-Siris syndrome	Likely benign (Apr 27, 2017)
19-10961163-C-T		Coffin-Siris syndrome	Likely benign (Mar 28, 2018)
19-10961185-C-T		Coffin-Siris syndrome	Uncertain significance (Jun 14, 2016)
19-10961203-C-T			Likely benign (Jul 01, 2023)
19-10961208-C-T		Rhabdoid tumor predisposition syndrome 2	Uncertain significance (May 28, 2019)
19-10961242-G-A			Likely benign (Jul 08, 2018)
19-10983915-C-T			Likely benign (Jun 23, 2018)
19-10984113-T-G			Uncertain significance (Feb 12, 2020)
19-10984115-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 15, 2022)
19-10984147-T-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Oct 29, 2018)
19-10984154-G-A		Neurodevelopmental disorder • Rhabdoid tumor predisposition syndrome 2	Uncertain significance (Jul 02, 2021)
19-10984157-C-T		not specified • Rhabdoid tumor predisposition syndrome 2 • Hereditary cancer-predisposing syndrome	Likely benign (Nov 14, 2023)
19-10984158-A-C		Rhabdoid tumor predisposition syndrome 2 • Hereditary cancer-predisposing syndrome • Intellectual disability, autosomal dominant 16	Uncertain significance (Jun 24, 2022)
19-10984158-A-G		Rhabdoid tumor predisposition syndrome 2	Uncertain significance (Feb 07, 2023)
19-10984159-C-A		Rhabdoid tumor predisposition syndrome 2 • Hereditary cancer-predisposing syndrome	Uncertain significance (Nov 29, 2022)
19-10984159-C-T		Rhabdoid tumor predisposition syndrome 2 • Hereditary cancer-predisposing syndrome	Uncertain significance (Sep 17, 2023)
19-10984160-T-C		Hereditary cancer-predisposing syndrome • Rhabdoid tumor predisposition syndrome 2	Likely benign (Mar 26, 2023)
19-10984161-C-G		Rhabdoid tumor predisposition syndrome 2 • Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 13, 2024)
19-10984161-C-T		Rhabdoid tumor predisposition syndrome 2	Uncertain significance (Jun 24, 2023)
19-10984162-C-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 17, 2021)
19-10984163-A-C		Hereditary cancer-predisposing syndrome	Likely benign (Feb 12, 2023)
19-10984164-G-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 14, 2022)
19-10984166-C-T		Rhabdoid tumor predisposition syndrome 2 • Hereditary cancer-predisposing syndrome	Likely benign (Dec 21, 2023)
19-10984168-C-A		Rhabdoid tumor predisposition syndrome 2	Uncertain significance (Oct 14, 2019)
19-10984169-A-G		Hereditary cancer-predisposing syndrome	Likely benign (Jul 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMARCA4	protein_coding	protein_coding	ENST00000429416	34	104474

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.10e-13	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.85	423	1.05e+3	0.404	0.0000773	10728
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000130	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Tumor suppressor activity of SMARCB1;Interleukin-7 signaling;Signaling by WNT;Signal Transduction;Gene expression (Transcription);Signaling by Interleukins;RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known;the information processing pathway at the ifn beta enhancer;Generic Transcription Pathway;Cytokine Signaling in Immune system;RNA Polymerase II Transcription;RMTs methylate histone arginines;Chromatin modifying enzymes;Immune System;TGF-beta super family signaling pathway canonical;Glucocorticoid receptor regulatory network;Chromatin organization;chromatin remodeling by hswi/snf atp-dependent complexes;Direct p53 effectors;TNFalpha;BMP2 signaling TGF-beta MV;BMP signaling Dro;Wnt Canonical;Regulation of nuclear beta catenin signaling and target gene transcription;Transcriptional regulation by RUNX1;Formation of the beta-catenin:TCF transactivating complex;TCF dependent signaling in response to WNT;Wnt Mammals;Validated nuclear estrogen receptor beta network;Regulation of retinoblastoma protein (Consensus)

Recessive Scores

• pRec: 0.506

Intolerance Scores

• loftool: 0.000689
• rvis_EVS: -2.85
• rvis_percentile_EVS: 0.6

Haploinsufficiency Scores

• pHI: 1.00
• hipred: Y
• hipred_score: 0.662
• ghis: 0.665

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Smarca4
• Phenotype: renal/urinary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; neoplasm; pigmentation phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype

Zebrafish Information Network

• Gene name: smarca4a
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;RNA polymerase I preinitiation complex assembly;neural retina development;chromatin organization;nucleosome disassembly;chromatin remodeling;regulation of transcription by RNA polymerase II;nervous system development;positive regulation of Wnt signaling pathway;negative regulation of cell growth;interleukin-7-mediated signaling pathway;ATP-dependent chromatin remodeling;positive regulation by host of viral transcription;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of DNA-binding transcription factor activity;negative regulation of androgen receptor signaling pathway;positive regulation of transcription of nucleolar large rRNA by RNA polymerase I;positive regulation of glucose mediated signaling pathway;positive regulation of pri-miRNA transcription by RNA polymerase II;beta-catenin-TCF complex assembly
• Cellular component: nuclear chromatin;extracellular space;nucleus;nucleoplasm;nucleolus;membrane;SWI/SNF complex;protein-containing complex;npBAF complex;nBAF complex
• 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;transcription corepressor activity;RNA binding;helicase activity;protein binding;ATP binding;DNA-dependent ATPase activity;transcription factor binding;Tat protein binding;nucleosomal DNA binding;protein N-terminus binding;androgen receptor binding;DNA polymerase binding;lysine-acetylated histone binding