Human Gene Module / Chromosome 19 / SMARCA4

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

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
10 / 0
Aliases
SMARCA4, BAF190,  BAF190A,  BRG1,  CSS4,  MRD16,  RTPS2,  SNF2,  SNF2L4,  SNF2LB,  SWI2,  hSNF2b
Associated Syndromes
Coffin-Siris syndrome-4 (CSS4)
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
19p13.2
Associated Disorders
-
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).

Reports related to SMARCA4 (6 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 literat... 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
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>G p.Pro143Ala missense_variant De novo - - 28714951 Lim ET , et al. (2017)
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.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.4543G>A p.Glu1515Lys missense_variant De novo - Simplex 28990276 Zhao JJ , et al. (2017)
c.1636_1638delAAG p.Lys546del inframe_deletion De novo - - 22426308 Tsurusaki Y , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Score remained at 3.3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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.
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
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
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).
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.
CNVs associated with SMARCA4(1 CNVs)
19p13.2 26 Deletion-Duplication 42  /  167
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