Human Gene Module / Chromosome 19 / SMARCA4

SMARCA4SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
11 / 24
Rare Variants / Common Variants
57 / 0
Aliases
SMARCA4, BAF190,  BAF190A,  BRG1,  CSS4,  MRD16,  RTPS2,  SNF2,  SNF2L4,  SNF2LB,  SWI2,  hSNF2b
Associated Syndromes
Coffin-Siris syndrome-4 (CSS4), Coffin-Siris syndrome-4, Coffin-Siris syndrome 4, DD, ID, epilepsy/seizures
Chromosome Band
19p13.2
Associated Disorders
ADHD, ASD
Relevance to Autism

Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4.

Molecular Function

The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family 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. Mutations in this gene are associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMARCA4 (24 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome Tsurusaki Y , et al. (2012) No -
2 Support Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literature Kosho T , et al. (2013) No -
3 Support Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A Kosho T , et al. (2014) No -
4 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
5 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
6 Support Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability Zhao JJ , et al. (2017) No Hypotonia, dysmorphic features
7 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
8 Support The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes? Li D et al. (2020) No ADHD, ASD
9 Support - Brunet T et al. (2021) No -
10 Support - Hiraide T et al. (2021) Yes -
11 Support - Mahjani B et al. (2021) Yes -
12 Support - Lee Y et al. (2021) No -
13 Recent Recommendation - Qian Y et al. (2021) No ASD or autistic features, ADHD
14 Support - Jin Y et al. (2022) No -
15 Support - England) (02/1) Yes -
16 Support - Hu C et al. (2022) Yes -
17 Support - Levchenko O et al. (2022) No Epilepsy/seizures
18 Support - Zhou X et al. (2022) Yes -
19 Support - Miyake N et al. (2023) Yes -
20 Support - Cirnigliaro M et al. (2023) Yes -
21 Support - Sanchis-Juan A et al. (2023) No -
22 Support - Lowther C et al. (2023) Yes -
23 Support - M Cecilia Poli et al. () No -
24 Support - Kirsten Furley et al. () No ID
Rare Variants   (57)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.715G>C p.Gly239Arg missense_variant Unknown - - 35699097 England) (02/1)
c.3310C>T p.Gln1104Ter stop_gained De novo - - 32686290 Li D et al. (2020)
c.4200C>G p.Ile1400Met stop_gained Unknown - - 32686290 Li D et al. (2020)
c.1018G>A p.Ala340Thr missense_variant Unknown - - 35699097 England) (02/1)
c.1351C>T p.Arg451Cys missense_variant De novo - - 32686290 Li D et al. (2020)
c.2477C>T p.Ala826Val missense_variant De novo - - 32686290 Li D et al. (2020)
c.2654G>A p.Arg885His missense_variant De novo - - 32686290 Li D et al. (2020)
c.2681C>T p.Thr894Met missense_variant De novo - - 32686290 Li D et al. (2020)
c.2851G>A p.Gly951Arg missense_variant De novo - - 32686290 Li D et al. (2020)
c.2900G>C p.Arg967Pro missense_variant Unknown - - 32686290 Li D et al. (2020)
c.2936G>A p.Arg979Gln missense_variant De novo - - 32686290 Li D et al. (2020)
c.1429A>G p.Asn477Asp missense_variant De novo - - 35741772 Hu C et al. (2022)
c.3508A>G p.Thr1170Ala missense_variant De novo - - 32686290 Li D et al. (2020)
c.3512T>G p.Val1171Gly missense_variant De novo - - 32686290 Li D et al. (2020)
c.3641T>C p.Ile1214Thr missense_variant De novo - - 32686290 Li D et al. (2020)
c.3728G>A p.Arg1243Gln missense_variant De novo - - 32686290 Li D et al. (2020)
c.1778_1780del p.Glu593del inframe_deletion Unknown - - 35699097 England) (02/1)
c.1273C>T p.Arg425Trp missense_variant Unknown - - 34813034 Qian Y et al. (2021)
c.1429A>G p.Asn477Asp missense_variant De novo - - 34813034 Qian Y et al. (2021)
c.2777A>G p.Asn926Ser missense_variant Unknown - - 34813034 Qian Y et al. (2021)
c.2900G>A p.Arg967His missense_variant De novo - - 34813034 Qian Y et al. (2021)
c.70C>G p.Pro24Ala missense_variant Familial Paternal - 35699097 England) (02/1)
c.3355C>T p.Arg1119Cys missense_variant De novo - - 34813034 Qian Y et al. (2021)
c.3476G>C p.Gly1159Ala missense_variant Unknown - - 34813034 Qian Y et al. (2021)
c.3730C>T p.Arg1244Cys missense_variant Unknown - - 34813034 Qian Y et al. (2021)
c.4213C>T p.Arg1405Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2460C>T p.Tyr820%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.602A>T p.Gln201Leu missense_variant Familial Paternal - 35699097 England) (02/1)
c.2437T>G p.Ser813Ala missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.3922C>T p.Arg1308Trp missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.2597A>T p.Asp866Val missense_variant Unknown - - 38536866 Kirsten Furley et al. ()
c.3712T>G p.Ser1238Ala missense_variant De novo - - 38177409 M Cecilia Poli et al. ()
c.326C>T p.Pro109Leu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.551T>C p.Ile184Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2576C>T p.Thr859Met missense_variant De novo - - 22426308 Tsurusaki Y , et al. (2012)
c.2653C>T p.Arg885Cys missense_variant De novo - - 22426308 Tsurusaki Y , et al. (2012)
c.2761C>T p.Leu921Phe missense_variant De novo - - 22426308 Tsurusaki Y , et al. (2012)
c.3128G>T p.Arg1043Leu missense_variant De novo - Simplex 34706719 Lee Y et al. (2021)
c.1365G>T p.Lys455Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2716C>T p.Arg906Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.427C>G p.Pro143Ala missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.3032T>C p.Met1011Thr missense_variant Unknown - - 22426308 Tsurusaki Y , et al. (2012)
c.3469C>G p.Arg1157Gly missense_variant De novo - - 22426308 Tsurusaki Y , et al. (2012)
c.1675G>A p.Glu559Lys missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.2282G>A p.Gly761Asp missense_variant Unknown Not maternal - 32686290 Li D et al. (2020)
c.4764C>T p.Val1588%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3236C>T p.Ser1079Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.4543G>A p.Glu1515Lys missense_variant De novo - Simplex 28990276 Zhao JJ , et al. (2017)
c.1537C>T p.Arg513Trp missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1636_1638del p.Lys546del inframe_deletion De novo - - 22426308 Tsurusaki Y , et al. (2012)
c.4309C>T p.Arg1437Trp missense_variant De novo - Multiplex 36973392 Miyake N et al. (2023)
c.2933G>A p.Arg978Gln missense_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.2681C>T p.Thr894Met missense_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.2936G>A p.Arg979Gln missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1199C>T p.Ala400Val missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4171-1754_4171-1753del - splice_site_variant Familial Paternal - 31452935 Feliciano P et al. (2019)
c.3411_3412insAACGGCCCGTTGGCATCGAGCCGCCGGCGCGCGGTTTCGAGCAC p.Leu1138AsnfsTer17 frameshift_variant De novo - Simplex 37595579 Lowther C et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
2
icon
1

Decreased from 2 to 1

1/1/2021
2
icon
2

Decreased from 2 to 2

Description

Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
7/1/2020
2
icon
2

Decreased from 2 to 2

Description

Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).

Reports Added
[The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2017
icon
3

Increased from to 3

Description

Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).

Krishnan Probability Score

Score 0.57176725654226

Ranking 751/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999999761183

Ranking 112/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.88

Ranking 167/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.56792349975214

Ranking 612/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.41135906664072

Ranking 1332/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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