ARID1A

protein-coding

AT-rich interaction domain 1A, the group of BAF complex|AT-rich interaction domain containing|Armadillo like helical domain containing

Gene summary

This gene encodes a member of the SWI/SNF family, whose members 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. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

C1orf4
SMARCF1

MANE transcript

NM_006015.6

Inheritance

ClinVar variants

P:161U:852B:775

Top phenotype

Coffin-Siris syndrome 2 (Mental retardation, autosomal dominant 14)

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr1:26,693,236-26,782,104

External References & Databases

Ensembl (ENSG00000117713)

Transcript & Mutation Effects

hg38 • Region Span ~88.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal dominant 14STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013819

Submitter: Illumina

The ARID1A gene is located on chromosome 1 at 1p36.11 and encodes the AT-rich interaction domain 1A. This protein is a component of the SWI/SNF complex and plays an important role in chromatin remodeling and DNA transcription, replication, and repair. It also functions in regulating neural stem cell fate and brain development. The ARID1A gene was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2012 (22426308: Tsurusaki et al. 2012). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight unique variants in this gene have been reported in at least three publications (22426308: Tsurusaki et al. 2012; 23929686: Santen et al. 2013; 23906836: Wieczorek et al. 2013). None of the variants were inherited, and at least three were proven de novo. The maximum score for genetic evidence has been reached. Loss of function is implicated as the mechanism of disease; all eight variants curated were heterozygous predicted null, although a truncated protein rather than nonsense-mediated decay was expected for three of the variants. This gene-disease relationship is supported by biochemical pathway (30123105: Bögershausen et al. 2018), protein interaction (20522713: Krosl et al. 2010), and animal model data (26806701: Chandler et al. 2016), as homozygous neural crest cell-specific null mice exhibit embryonic lethality but also features that overlap with the human disease. Heterozyous conditional null mice also partially recapitulate the phenotype. In summary, there is strong evidence to support the relationship between ARID1A and Coffin-Siris syndrome (autosomal dominant). Additional reports in human published after the first proposal of the association are needed to reach a definitive classification.

Coffin-Siris syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: ClinGen

ARID1A was initially reported in relation to Coffin-Siris syndrome (CSS), a condition characterized by varying degrees of intellectual disability, characteristic facial features, atypical hair patterns (sparse scalp hair but hypertrichosis on other areas of the body), and digital abnormalities, in 2012 (PMID: 22426308). At least 14 probands have been reported in the literature; variants were de novo in all subjects with available parental DNA (PMIDs: 23906836, 23929686, 31530938). While most reported variants were truncating variants, at least one missense variant has been reported in an individual with features consistent with CSS (PMID: 31530938). Several of the reported variants have been found to be mosaic in the probands. There is experimental evidence to support this gene-disease relationship, including data showing that ARID1A interacts with proteins in the BRG1-associated factor (BAF) complex; genes encoding for other proteins within this complex, such as ARID1B, SMARCA4, and SMARCB1, have also been associated with CSS (PMID: 32001526). Mice with heterozygous loss of ARID1A in neural crest cells exhibit mild craniofacial defects (PMID: 26806701). In summary, there is definitive evidence supporting a relationship between ARID1A and CSS. This curation was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 2021/07/07 (SOP Version 8).

intellectual disability, autosomal dominant 14STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013819

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal dominant 14DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013819

Submitter: G2P

Coffin-Siris syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: Orphanet

intellectual disability, autosomal dominant 14STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013819

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Coffin-Siris syndrome 2 (Mental retardation, autosomal dominant 14)AD

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; 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: 22426308; 22426309

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARID1A variants in ClinVar

32 Conditions Cataloged

not providedTotal: 1491

not specifiedTotal: 237

Inborn genetic diseasesTotal: 232

Intellectual disability, autosomal dominant 14Total: 229

ARID1A-related disorderTotal: 176

Malignant tumor of urinary bladderTotal: 21

Coffin-Siris syndromeTotal: 12

ARID1A-related BAFopathyTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006015.6. 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		1 clinvar	20 clinvar	391 clinvar	54 clinvar	466
missense	3 clinvar	37 clinvar	741 clinvar	246 clinvar	84 clinvar	1111
nonsense	51 clinvar	7 clinvar	32 clinvar			90
start loss			2 clinvar			2
frameshift	35 clinvar	17 clinvar	43 clinvar			95
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	14 clinvar			24
Total	91	70	852	637	138	1788

Highest pathogenic variant AF is 0.000016736734

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006015.6	RefSeq	NP_006006.3	20	MANE Select
ENST00000324856.13	Ensembl	ENSP00000320485.7	20	MANE Select
NM_139135.4	RefSeq	NP_624361.1	20	Standard
ENST00000374152.7	Ensembl	ENSP00000363267.2	19	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)
miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

negative regulation of transcription by RNA polymerase II
formation of primary germ layer
neural tube closure
cardiac chamber development
optic cup formation involved in camera-type eye development

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
transcription coactivator activity
protein binding
nuclear receptor binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
SWI/SNF complex
npBAF complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324856
Coding exons: 20
Length: 86072
Individuals with no LoFs: 125745
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125747
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.66	823	1.18e+3	0.700	0.0000669	14782
Missense (PolyPhen)		44	120.16	0.36619		1335
Synonymous	-1.27	494	459	1.08	0.0000269	4683
Loss of Function	8.55	2	89.0	0.0225	0.00000473	980

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
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: 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. Binds DNA non-specifically. 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:A2BH40, ECO:0000303|PubMed:12672490, ECO:0000303|PubMed:22952240, ECO:0000303|PubMed:26601204}.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.0215
RVIS EVS: -2.67
RVIS percentile EVS: 0.74

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

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