Human Gene Module / Chromosome 16 / SRCAP

SRCAPSnf2 related CREBBP activator protein

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
40 / 0
Aliases
SRCAP, DOMO1,  EAF1,  FLHS,  SWR1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
16p11.2
Associated Disorders
ID, ASD, ADHD
Relevance to Autism

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Rots et al., 2021 reported 33 unrelated individuals with truncating SRCAP variants proximal (n=28) or distal (n=5) to the locus for Floating-Harbor syndrome who presented with a distinct neurodevelopmental disorder characterized by developmental delay with or without intellectual disability, behavioral and psychiatric abnormalities, non-specific facial features, musculoskeletal abnormalities, and hypotonia; autism spectrum disorder was observed in individuals with both proximal SRCAP variants (10/24; 41.67%) and distal SRCAP variants (2/5; 40%) in this report.

Molecular Function

This gene encodes the core catalytic component of the multiprotein chromatin-remodeling SRCAP complex. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It can function as a transcriptional activator in Notch-mediated, CREB-mediated and steroid receptor-mediated transcription. Mutations in this gene cause Floating-Harbor syndrome (OMIM 136140), a rare disorder characterized by short stature, language deficits and dysmorphic facial features.

Reports related to SRCAP (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
6 Recent Recommendation - Rots D et al. (2021) No ASD, ADHD, ID
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.55-1G>A - splice_site_variant De novo NA - 33909990 Rots D et al. (2021)
c.3893-2A>G - splice_site_variant De novo NA - 33909990 Rots D et al. (2021)
c.1174C>T p.Gln392Ter stop_gained De novo NA - 33909990 Rots D et al. (2021)
c.2518C>T p.Arg840Ter stop_gained De novo NA - 33909990 Rots D et al. (2021)
c.3833C>A p.Ser1278Ter stop_gained De novo NA - 33909990 Rots D et al. (2021)
c.4925T>A p.Leu1642Ter stop_gained De novo NA - 33909990 Rots D et al. (2021)
c.6208C>T p.Arg2070Ter stop_gained De novo NA - 33909990 Rots D et al. (2021)
c.148del p.His50ThrfsTer2 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5527del p.Val1843PhefsTer9 frameshift_variant Unknown - - 33909990 Rots D et al. (2021)
c.7002G>C p.Gln2334His missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.2494-2A>G - splice_site_variant De novo NA Simplex 28191889 Stessman HA , et al. (2017)
c.435del p.Gln145HisfsTer25 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.1793del p.Gly598ValfsTer9 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.833del p.Pro278LeufsTer102 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.6901del p.Glu2301LysfsTer6 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.9126dup p.Gln3043AlafsTer9 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.4648del p.Val1550CysfsTer34 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5387del p.Pro1796LeufsTer56 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5633dup p.Pro1879ThrfsTer21 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.6889del p.Arg2297GlyfsTer10 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.9344del p.Pro3115GlnfsTer13 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5633dupC p.Pro1879ThrfsTer21 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5179A>T p.Thr1727Ser missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.5809G>A p.Gly1937Ser missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.9338_9341del p.Leu3113ProfsTer14 frameshift_variant Unknown - - 33909990 Rots D et al. (2021)
c.4200_4204del p.Leu1401ArgfsTer23 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.4557_4560del p.Gln1519HisfsTer18 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5549_5556del p.Thr1850IlefsTer47 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5977_5980del p.Cys1993ThrfsTer42 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5461delinsAGA p.Ser1821ArgfsTer32 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.5984del p.Pro1995HisfsTer41 frameshift_variant Familial Paternal - 33909990 Rots D et al. (2021)
c.1608_1611delinsCA p.Gln537LysfsTer5 frameshift_variant De novo NA - 33909990 Rots D et al. (2021)
c.9364del p.Leu3122CysfsTer6 frameshift_variant Unknown Not maternal - 33909990 Rots D et al. (2021)
c.8592dup p.Lys2865GlnfsTer15 frameshift_variant Unknown Not paternal - 33909990 Rots D et al. (2021)
c.5633dupC p.Pro1879ThrfsTer21 frameshift_variant Unknown Not maternal - 33909990 Rots D et al. (2021)
c.6409del p.Asp2137ThrfsTer41 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.5102_5103del p.Ser1701PhefsTer146 frameshift_variant Familial Maternal - 33909990 Rots D et al. (2021)
c.5972_5975del p.His1991ProfsTer44 frameshift_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.450C>G p.Asp150Glu missense_variant De novo NA - 25533962 Deciphering Developmental Disorders Study (2014)
c.1143_1153delinsTGT p.Pro382ValfsTer14 frameshift_variant Unknown Not maternal - 33909990 Rots D et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Score Delta: Score remained at 2

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.

4/1/2021
2
icon
2

Score remained at 2

Description

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[New Scoring Scheme]
4/1/2017
3
icon
2

Decreased from 3 to 2

Description

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

1/1/2017
icon
3

Increased from to 3

Description

A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017.

Krishnan Probability Score

Score 0.45721839202447

Ranking 9790/25841 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 0.99999999707556

Ranking 118/18225 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 0.975

Ranking 51/239 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 0.53810001687653

Ranking 535/18665 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 0.3088309342057

Ranking 2612/20870 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 SRCAP(1 CNVs)
16p11.2 120 Deletion-Duplication 184  /  1584
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