Human Gene Module / Chromosome 12 / EP400

EP400E1A binding protein p400

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 11
Rare Variants / Common Variants
68 / 0
Aliases
EP400, CAGH32,  DKFZP434I225,  FLJ42018,  FLJ45115,  P400,  TNRC12
Associated Syndromes
-
Chromosome Band
12q24.33
Associated Disorders
-
Relevance to Autism

A compound heterozygous mutation in the EP400 gene was identified in an ASD proband from a nonconsanguineous family that showed evidence of distant shared ancestry as identified by homozygosity analysis (Chahrour et al., 2012). A de novo missense variant in the gene was subseuqently identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012).

Molecular Function

Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. May be required for transcriptional activation of E2F1 and MYC target genes during cellular proliferation. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. May regulate ZNF42 transcription activity. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AFZ from the nucleosome.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EP400 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism Chahrour MH , et al. (2012) Yes -
2 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
6 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Recent Recommendation - Pollina EA et al. (2023) No -
10 Support - Hu C et al. (2023) Yes -
11 Support - Axel Schmidt et al. (2024) No Autistic behavior
Rare Variants   (68)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.980T>G p.Val327Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1335+1573C>T - intron_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3650A>G p.Asn1217Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6885G>C p.Glu2295Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1258C>T p.Gln420Ter stop_gained Unknown - - 39039281 Axel Schmidt et al. (2024)
c.3771C>T p.Val1257%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6879C>T p.Arg2293%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.7453C>T p.Arg2485Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.175C>T p.Gln59Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1088A>C p.Gln363Pro missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1190A>G p.Gln397Arg missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.8411C>T p.Pro2804Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.428C>T p.Pro143Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1117T>C p.Tyr373His missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5493G>A p.Glu1831%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8166G>A p.Gln2722%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3889A>G p.Lys1297Glu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5818C>T p.Arg1940Cys missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.4324G>A p.Val1442Met missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3630G>A p.Leu1210%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5923G>A p.Gly1975Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2242C>T p.Arg748Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2597A>C p.Lys866Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2818G>A p.Ala940Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3138T>C p.Asn1046%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3041G>A p.Gly1014Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8006C>T p.Ala2669Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8408C>T p.Ala2803Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8863G>A p.Val2955Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8926G>A p.Ala2976Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1335+1644C>T - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.842_859dup p.Gln281_Pro286dup inframe_insertion De novo - Simplex 35982159 Zhou X et al. (2022)
c.8854C>T p.Pro2952Ser stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.214G>A p.Val72Met missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4090C>T p.Leu1364= missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2035G>C p.Gly679Arg missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2460A>C p.Glu820Asp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.88dup p.Ala30GlyfsTer35 frameshift_variant Familial - Multiplex 25363760 De Rubeis S , et al. (2014)
c.3388C>T p.Leu1130Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3850T>C p.Tyr1284His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4031G>A p.Gly1344Asp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4352G>A p.Arg1451Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4544C>G p.Pro1515Arg missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5338A>C p.Thr1780Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5437C>T p.Arg1813Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5616G>C p.Gln1872His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5774A>G p.Asn1925Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5942A>G p.His1981Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6097C>T p.Pro2033Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6436G>A p.Glu2146Lys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7535C>T p.Pro2512Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7945G>A p.Gly2649Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7945G>A p.Gly2649Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7958C>T p.Thr2653Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8006C>T p.Ala2669Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8071C>T p.Arg2691Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8149C>T p.Leu2717Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8429A>C p.Gln2810Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8429A>C p.Gln2810Pro missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8453C>T p.Pro2818Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8986C>G p.Leu2996Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.85_86insG p.Pro29ArgfsTer36 frameshift_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.8429A>C p.Gln2810Pro missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.85_86insG p.Pro29ArgfsTer36 frameshift_variant Familial - Multiplex 25363760 De Rubeis S , et al. (2014)
c.4945G>A p.Ala1649Thr missense_variant Familial - Extended multiplex 22511880 Chahrour MH , et al. (2012)
c.6097C>T p.Pro2033Ser missense_variant Familial - Extended multiplex 22511880 Chahrour MH , et al. (2012)
c.1844_1847dup p.Gln617LeufsTer75 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo probably damaging missense variant and a de novo LoF variant was observed in EP400 in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (Iossifov et al., 2012; De Rubeis et al., 2014). This gene was subsequently identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo probably damaging missense variant and a de novo LoF variant was observed in EP400 in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (Iossifov et al., 2012; De Rubeis et al., 2014). This gene was subsequently identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo probably damaging missense variant and a de novo LoF variant was observed in EP400 in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (Iossifov et al., 2012; De Rubeis et al., 2014). This gene was subsequently identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo probably damaging missense variant and a de novo LoF variant was observed in EP400 in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (Iossifov et al., 2012; De Rubeis et al., 2014). This gene was subsequently identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
icon
3

Increased from to 3

Description

A de novo probably damaging missense variant and a de novo LoF variant was observed in EP400 in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (Iossifov et al., 2012; De Rubeis et al., 2014). This gene was subsequently identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
Krishnan Probability Score

Score 0.49514487628269

Ranking 3168/25841 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 0.9999999998832

Ranking 73/18225 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 0.98

Ranking 45/239 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 0.42979785476614

Ranking 320/18665 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
Larsen Cumulative Evidence Score

Score 54.5

Ranking 29/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.44866049200774

Ranking 938/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ALAS1 aminolevulinate, delta-, synthase 1 Human Protein Binding 211 P13196
Col4a1 collagen, type IV, alpha 1 Mouse DNA Binding 12826 P02463
E1A Early E1A 29.5 kDa protein HCoV-OC43 Protein Binding 1460853 P03259
E2 Regulatory protein E2 Protein Binding 1489080 P03120
FOXR1 Forkhead box protein R1 Human Protein Binding 283150 Q6PIV2
FOXR2 Forkhead box protein R2 Human Protein Binding 139628 Q6PJQ5
Gata6 GATA binding protein 6 Mouse DNA Binding 14465 Q61169
HIST1H2BA Histone H2B type 1-A Human Protein Binding 255626 Q96A08
MAX MYC associated factor X Human Protein Binding 4149 P61244
MDC1 mediator of DNA-damage checkpoint 1 Human DNA Binding 9656 A1Z5I9
MZF1 myeloid zinc finger 1 Human Protein Binding 7593 P28698
NS3 Envelope small membrane protein HCoV-OC43 Protein Binding 2648206 Q04854
SSX3 Protein SSX3 Human Protein Binding 10214 Q99909
TAT tyrosine aminotransferase Human Protein Binding 6898 P17735
TBC1D4 TBC1 domain family, member 4 Human Protein Binding 9882 O60343
UL27 Envelope glycoprotein B HHV-1 Protein Binding 2703455 P10211
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