Human Gene Module / Chromosome 16 / SRCAP

SRCAPSnf2 related CREBBP activator protein

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
11 / 17
Rare Variants / Common Variants
67 / 0
Aliases
SRCAP, DOMO1,  EAF1,  FLHS,  SWR1
Associated Syndromes
-
Chromosome Band
16p11.2
Associated Disorders
ADHD, ID, ASD
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. Additional de novo loss-of-function and missense variants in the SRCAP gene were observed in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; furthermore, a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified SRCAP as a gene reaching exome-wide significance (P < 2.5E-06). 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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SRCAP (17 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
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Brea-Fernández AJ et al. (2022) No -
9 Recent Recommendation - Zhou X et al. (2022) Yes -
10 Support - Yuan B et al. (2023) Yes -
11 Support - Spataro N et al. (2023) No Stereotypy
12 Support - Hu C et al. (2023) Yes -
13 Support - Sanchis-Juan A et al. (2023) No -
14 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
15 Support - Kirsten Furley et al. () No -
16 Support - Chaodong Ding et al. (2024) Yes -
17 Support - Ruohao Wu et al. (2024) Yes -
Rare Variants   (67)
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 - - 33909990 Rots D et al. (2021)
c.3893-2A>G - splice_site_variant De novo - - 33909990 Rots D et al. (2021)
c.2494-2A>G - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1174C>T p.Gln392Ter stop_gained De novo - - 33909990 Rots D et al. (2021)
c.2518C>T p.Arg840Ter stop_gained De novo - - 33909990 Rots D et al. (2021)
c.1849C>T p.Gln617Ter stop_gained De novo - - 36881370 Yuan B et al. (2023)
c.3833C>A p.Ser1278Ter stop_gained De novo - - 33909990 Rots D et al. (2021)
c.4925T>A p.Leu1642Ter stop_gained De novo - - 33909990 Rots D et al. (2021)
c.6208C>T p.Arg2070Ter stop_gained De novo - - 33909990 Rots D et al. (2021)
c.7330C>T p.Arg2444Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.1799C>T p.Thr600Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.282C>T p.Ala94%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.7303C>T p.Arg2435Ter stop_gained Unknown - - 38536866 Kirsten Furley et al. ()
c.5293G>C p.Ala1765Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6451C>T p.Arg2151Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7028G>C p.Arg2343Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8388G>A p.Met2796Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8975C>T p.Thr2992Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8984C>G p.Thr2995Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.9361C>T p.Arg3121Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.148del p.His50ThrfsTer2 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.6985C>T p.Arg2329Ter stop_gained De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.7002G>C p.Gln2334His missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2494-2A>G - splice_site_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.4451T>A p.Val1484Asp missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.435del p.Gln145HisfsTer25 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.1793del p.Gly598ValfsTer9 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5821C>T p.Pro1941Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8381G>A p.Arg2794His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.833del p.Pro278LeufsTer102 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5527del p.Val1843PhefsTer9 frameshift_variant Unknown - - 33909990 Rots D et al. (2021)
c.6901del p.Glu2301LysfsTer6 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.9126dup p.Gln3043AlafsTer9 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.4648del p.Val1550CysfsTer34 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5387del p.Pro1796LeufsTer56 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5633dup p.Pro1879ThrfsTer21 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.6889del p.Arg2297GlyfsTer10 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.9344del p.Pro3115GlnfsTer13 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5161del p.Ala1721HisfsTer48 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5258del p.Pro1753LeufsTer16 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5633dupC p.Pro1879ThrfsTer21 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.7300G>T p.Glu2434Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.6805G>A p.Ala2269Thr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5179A>T p.Thr1727Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5809G>A p.Gly1937Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4628C>T p.Pro1543Leu missense_variant Familial Paternal - 36980980 Spataro N et al. (2023)
c.4200_4204del p.Leu1401ArgfsTer23 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.4557_4560del p.Gln1519HisfsTer18 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5549_5556del p.Thr1850IlefsTer47 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.5977_5980del p.Cys1993ThrfsTer42 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.9338_9341del p.Leu3113ProfsTer14 frameshift_variant Unknown - - 33909990 Rots D et al. (2021)
c.7096_7102del p.Ala2366MetfsTer107 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5461delinsAGA p.Ser1821ArgfsTer32 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.7488_7489insG p.Pro2497AlafsTer46 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1608_1611delinsCA p.Gln537LysfsTer5 frameshift_variant De novo - - 33909990 Rots D et al. (2021)
c.6710A>C p.Gln2237Pro missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.5984del p.Pro1995HisfsTer41 frameshift_variant Familial Paternal - 33909990 Rots D et al. (2021)
c.7273dup p.Thr2425AsnfsTer18 frameshift_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.9364del p.Leu3122CysfsTer6 frameshift_variant Unknown Not maternal - 33909990 Rots D et al. (2021)
c.6409del p.Asp2137ThrfsTer41 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
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.5102_5103del p.Ser1701PhefsTer146 frameshift_variant Familial Maternal - 33909990 Rots D et al. (2021)
c.5972_5975del p.His1991ProfsTer44 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.450C>G p.Asp150Glu missense_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.7275_7282dup p.Arg2428HisfsTer50 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
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

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.

4/1/2021
1
icon
1

Score remained at 1

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
[Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature2021]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
CNVs associated with SRCAP(1 CNVs)
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16p11.2 145 Deletion-Duplication 212  /  1657
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