GeneBe

SMARCC1

protein-coding

SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1, the group of BAF complex|GBAF complex|PBAF complex|Myb/SANT domain containing|Small nucleolar RNA protein coding host genes

Gene summary

The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which 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 and contains a predicted leucine zipper motif typical of many transcription factors. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003074.4

Inheritance

AD

ClinVar variants

P:18U:195B:29

Top phenotype

Hydrocephalus, congenital, 5, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr3:47,585,269-47,782,106

External References & Databases

Ensembl (ENSG00000173473)NCBI Gene (6599)OMIM (601732)HGNC:11104GenCCUniProt (Q92922)AlphaFoldClinVar (SMARCC1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~196.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SMARCC1-associated developmental dysgenesis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700123

Submitter: PanelApp Australia

hydrocephalus, congenital, 5, susceptibility toMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859376

Submitter: Ambry Genetics

hydrocephalus, congenital, 5, susceptibility toSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859376

Submitter: Labcorp Genetics (formerly Invitae)

SMARCC1-associated developmental dysgenesis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700123

Submitter: ClinGen

SMARCC1 was first reported in relation to autosomal dominant SMARCC1-associated developmental dysgenesis syndrome in 2018 (Al Mutairi et al., PMID: 29360170). SMARCC1-associated developmental dysgenesis syndrome is characterized by developmental delay, cerebral ventriculomegaly, aqueductal stenosis, and other associated structural brain and cardiac defects. Nine variants (missense, canonical splice site, nonsense, and frameshift) that have been reported in nine probands in four publications (PMIDs: 29360170, 29983323, 33077954, 34906496) are included in this curation. Variants are inherited primarily de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression in the neuroepithelium and ventricular zone during neurogenesis (PMID: 29983323), biochemical function important for the BAF chromatin remodeling complex during human brain morphogenesis (PMID: 36993720), and two homozygous mouse models with brain abnormalities (PMIDs: 11604513, 24170322). In summary, there is definitive evidence supporting the relationship between SMARCC1 and autosomal dominant SMARCC1-associated developmental dysgenesis 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 Brain Malformations GCEP on the meeting date April 11, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Hydrocephalus, congenital, 5, susceptibility toAD

Manifestation: 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: 29983323; 33077954Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMARCC1 variants in ClinVar

9 Conditions Cataloged
Inborn genetic diseasesTotal: 128
not providedTotal: 65
SMARCC1-related disorderTotal: 30
Hydrocephalus, congenital, 5, susceptibility toTotal: 9
Congenital hydrocephalusTotal: 6
not specifiedTotal: 4
SMARCC1-associated developmental dysgenesis syndromeTotal: 3
Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003074.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
18
clinvar
1
clinvar
 26
missense
2
clinvar
167
clinvar
9
clinvar
1
clinvar
 179
nonsense
1
clinvar
8
clinvar
4
clinvar
 13
start loss
0
frameshift
1
clinvar
6
clinvar
9
clinvar
 16
splice donor/acceptor (+/-2bp)
8
clinvar
 8
Total216195272242

Highest pathogenic variant AF is 0.00000288465

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 91 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003074.4RefSeqNP_003065.328MANE Select
ENST00000254480.10EnsemblENSP00000254480.528MANE Select
ENST00000454240.1EnsemblENSP00000414266.14Standard
ENST00000855762.1EnsemblENSP00000525821.128Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
smarcc1aDanio rerio

Structure: heart

Quality: morphology

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
  • Tumor suppressor activity of SMARCB1
  • Gene expression (Transcription)

Biological Process

  • nucleosome disassembly
  • chromatin remodeling
  • regulation of transcription by RNA polymerase II
  • nervous system development
  • insulin receptor signaling pathway

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
  • transcription coactivator activity
  • protein binding

Cellular Component

  • nuclear chromatin
  • XY body
  • nucleus
  • nucleoplasm
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000254480
Coding exons
28
Length
196835
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
12
Defined
125747
p
0.0000477
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.454386080.7210.00003207242
Missense (PolyPhen)78174.420.447192095
Synonymous0.2382122160.9790.00001182091
Loss of Function7.23366.70.04500.00000364765

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.0000580.000054rare
Finnish0.0000490.000046rare
European (Non-Finnish)0.0000560.000053rare
South Asian0.0000330.000033rare
Other00.0absent

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. May stimulate the ATPase activity of the catalytic subunit of the complex (PubMed:10078207, PubMed:29374058). 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). {ECO:0000250|UniProtKB:P97496, ECO:0000269|PubMed:10078207, ECO:0000269|PubMed:11018012, ECO:0000269|PubMed:29374058, ECO:0000303|PubMed:22952240, ECO:0000303|PubMed:26601204}.;

Intolerance Scores

LoFtool
0.186
RVIS EVS
-0.84
RVIS percentile EVS
11.28

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.999

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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