SMARCE1

Chr 17AD

SWI/SNF related BAF chromatin remodeling complex subunit E1

ENSG00000073584 UniProt: Q969G3 OMIM: 603111

The encoded protein is a component of the SWI/SNF chromatin remodeling complex that binds to 4-way junction DNA and enables transcriptional activation of genes normally repressed by chromatin. Loss-of-function mutations cause Coffin-Siris syndrome 5, a neurodevelopmental disorder characterized by intellectual disability, distinctive facial features, and hypoplastic fifth fingernails and toenails, following an autosomal dominant inheritance pattern. Mutations also predispose to familial meningioma.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.192 OMIM phenotypes

Clinical Summary— SMARCE1

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Gene-Disease Validity (ClinGen)

familial meningioma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.44

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.74Z-score

OE missense 0.51 (0.44–0.59)

123 obs / 243.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.51 (0.44–0.59)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 1 / 24.9Missense obs/exp: 123 / 243.3Syn Z: 0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSMARCE1-related Coffin SirisOTHERAD

definitiveSMARCE1-related meningioma, familialLOFAD

This gene — mechanism propensity

0.3793th %ile

GOF

0.3690th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.19 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNMutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.1

LOFLoss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References