SMARCE1
protein-codingSWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1, the group of BAF complex|PBAF complex
Gene summary
The protein encoded by this gene is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. The encoded protein, either alone or when in the SWI/SNF complex, can bind to 4-way junction DNA, which is thought to mimic the topology of DNA as it enters or exits the nucleosome. The protein contains a DNA-binding HMG domain, but disruption of this domain does not abolish the DNA-binding or nucleosome-displacement activities of the SWI/SNF complex. Unlike most of the SWI/SNF complex proteins, this protein has no yeast counterpart. [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 ~23.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014838
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014838
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011789
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016995
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011789
Submitter: ClinGen
SMARCE1 (the encoded protein is referred to as BAF57) was first reported in relation to autosomal dominant familial clear cell meningioma in 2013 by Smith et al., PMID:23377182. At least 9 unique variants (most inherited truncating variants often with a second variant (truncating or LOH in the tumor) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and trio or pedigree data. Pedigrees reported thus far do not yield scorable segregation data, although autosomal dominant inheritance with incomplete penetrance (in males) is apparent in the familial studies reported. While there is no definitive penetrance estimation in literature and the mechanism of sex-biased penetrance is unknown, Smith et al PMID:23377182 notes that in a cohort of 13 individuals with clear cell spinal meningiomas from 9 families, 12 are female. A total of 11 points curated from 5 publications (PMIDS:23377182, 25143307, 26803492, 27891692, 30421029) are described. Experimental work shows lack of SMARCE1 expression in mengioma tumors (PMID:23377182, 27891692) as well as normal expression in non-tumor tissues with multiple isoforms expressed in brain and neuronal tissues (PMID:19245665). Reports display the role of BAF57 in CD4/CD8 regulation in T-cell lineage (PMID: 12110891), androgen (PMC:1061596) or estrogen (PMC:126156) receptor interaction, cell cycle regulation (PMID:16135788), and interaction with transcriptional repressors in neuronal progenitor cells (PMID: 31428904). However, functional studies in patient or non-patient cell lines, and animal models that directly relate to familial meningioma were not identified. Lomeli et al (PMID:27149204) provides a thorough review of BAF57 molecular and genetic studies up to 2016 and no further experimental studies directly relating to familial meningioma were identified between 2016 and present (2020). Currently the functional/causal roles of SMARCE1 in familial meningioma are overall experimentally unknown although a total of 2 pts were curated from 3 publications (PMIDS:23377182, 27891692, 19245665). Based on extensive genetic evidence as well as experimental expression evidence, and replication since the time of publication in 2013, SMARCE1 is definitively associated with autosomal dominant familial clear cell meningioma.
Inheritance Pattern: AD
Disease ID:MONDO:0014838
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014838
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015452
Submitter: ClinGen
SMARCE1 is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. *SMARCE1* was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2012 (Tsurusaki et al., PMID: 22426308). Coffin-Siris syndrome is a rare congenital disorder characterized by delayed psychomotor development, intellectual disability, coarse facial features, and hypoplasia of the distal phalanges, particularly the fifth digit. Other features may also be observed, including congenital heart defects, hypoplasia of the corpus callosum, and poor overall growth with short stature and microcephaly (PMID: 23906836). Of note, variants in *SMARCE1* have also been reported in autosomal dominant familial meningioma; this gene disease-relationship has been curated separately. Seven variants (6 missense and 1 splice variant leading to an in-frame deletion) reported in 13 probands in 11 publications (PMIDs: 22426308, 23906836, 23929686, 27264197, 30499906, 30548424, 31273213, 31530938, 31675646, 32732226, 37853563) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most reported variants occur *de novo*. Several variants are recurrent (including p.Tyr73Ser, p.Tyr73Cys and p.Arg105Gln), and most cluster within the HMG domain of the SMARCE1 protein. The fact that all reported variants are either missense or in-frame deletions is consistent with a gain-of-function or dominant-negative effect, but no functional studies have been performed. This gene-disease relationship is also supported by experimental evidence, including biochemical function and protein interactions. Several other members of the SWI/SNF complex have been involved in Coffin-Siris syndrome, including *SMARCA4*, *SMARCB1*, *SMARCC2*, *SMARCD1*, *DPF2*, *ARID1A*, *ARID1B*, *ARID2* and *BICRA*. Variants in *SMARCA2*, another member of the SWI/SNF complex, cause a related disorder, Nicolaides-Baraitser syndrome. In summary, there is definitive evidence supporting the relationship between *SMARCE1* 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 approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panels on September 18, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0011789
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015452
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Oncologic
Intervention: Oncologic
Rationale: Awareness of the risk of neoplasms may allow early detection and treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMARCE1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003079.5. 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 | 7 | 294 | 301 | |||
| missense | 6 | 9 | 485 | 102 | 602 | |
| nonsense | 16 | 1 | 5 | 1 | 23 | |
| start loss | 2 | 2 | ||||
| frameshift | 25 | 10 | 14 | 49 | ||
| splice donor/acceptor (+/-2bp) | 2 | 13 | 11 | 26 | ||
| Total | 49 | 33 | 524 | 397 | 0 | 1003 |
Highest pathogenic variant AF is 0.000001369469
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003070.3 | 10 | MANE Select | |
| Ensembl | ENSP00000323967.6 | 10 | MANE Select | |
| Ensembl | ENSP00000466608.2 | 10 | Standard | |
| Ensembl | ENSP00000466608.2 | 10 | Standard |
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 signaling pathway
- Pathways Affected in Adenoid Cystic Carcinoma
- Tumor suppressor activity of SMARCB1
Biological Process
- nucleosome disassembly
- chromatin remodeling
- regulation of transcription by RNA polymerase II
- neurogenesis
- ATP-dependent chromatin remodeling
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- chromatin binding
- transcription coactivator activity
Cellular Component
- nuclear chromosome
- nuclear chromatin
- nucleus
- nucleoplasm
- SWI/SNF complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000348513
- Coding exons
- 10
- Length
- 23547
- Individuals with no LoFs
- 125665
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125666
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.74 | 123 | 243 | 0.506 | 0.0000141 | 2736 |
| Missense (PolyPhen) | 5 | 14.884 | 0.33592 | 152 | ||
| Synonymous | 0.281 | 83 | 86.3 | 0.962 | 0.00000557 | 722 |
| Loss of Function | 4.44 | 1 | 24.9 | 0.0402 | 0.00000139 | 278 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- 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. 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 (By similarity). Required for the coactivation of estrogen responsive promoters by SWI/SNF complexes and the SRC/p160 family of histone acetyltransferases (HATs). Also specifically interacts with the CoREST corepressor resulting in repression of neuronal specific gene promoters in non-neuronal cells. {ECO:0000250|UniProtKB:O54941, ECO:0000303|PubMed:12672490, ECO:0000303|PubMed:22952240, ECO:0000303|PubMed:26601204}.;
- Disease
- DISEASE: Meningioma (MNGMA) [MIM:607174]: A common neoplasm of the central nervous system derived from arachnoidal cells. The majority of meningiomas are well differentiated vascular tumors which grow slowly and have a low potential to be invasive, although malignant subtypes occur. Most cases are sporadic. Familial occurrence of meningioma is rare. {ECO:0000269|PubMed:23377182, ECO:0000269|PubMed:25249420}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Coffin-Siris syndrome 5 (CSS5) [MIM:616938]: 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, ECO:0000269|PubMed:23906836}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.178
Intolerance Scores
- LoFtool
- 0.0639
- RVIS EVS
- -0.01
- RVIS percentile EVS
- 53.51
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |