Human Gene Module / Chromosome 7 / TRRAP

TRRAPtransformation/transcription domain associated protein

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 8
Rare Variants / Common Variants
41 / 0
Aliases
TRRAP, PAF350/400,  PAF400,  STAF40,  TR-AP,  Tra1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
7q22.1
Associated Disorders
ASD
Relevance to Autism

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Molecular Function

This gene encodes a large multidomain protein of the phosphoinositide 3-kinase-related kinases (PIKK) family. The encoded protein is a common component of many histone acetyltransferase (HAT) complexes and plays a role in transcription and DNA repair by recruiting HAT complexes to chromatin.

Reports related to TRRAP (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
3 Support Prevalence and architecture of de novo mutations in developmental disorders. Deciphering Developmental Disorders Study (2017) No -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
5 Support De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive dis... Mavros CF , et al. (2018) No -
6 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Coe BP , et al. (2018) No -
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
8 Recent Recommendation Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. Cogn B , et al. (2019) No ASD
Rare Variants   (41)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3127G>A p.Ala1043Thr missense_variant De novo NA - 30827496 Cogn B , et al. (2019)
c.6415T>C p.Trp2139Arg missense_variant De novo NA - 30827496 Cogn B , et al. (2019)
c.2087G>A p.Arg696His missense_variant Unknown - Simplex 30564305 Guo H , et al. (2018)
c.6011G>A p.Arg2004Gln missense_variant De novo NA - 30424743 Mavros CF , et al. (2018)
c.2413C>T p.Leu805Phe missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.2580C>G p.Phe860Leu missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.2678G>T p.Arg893Leu missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.3093T>G p.Ile1031Met missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.3104G>A p.Arg1035Gln missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.3127G>A p.Ala1043Thr missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.3311A>G p.Glu1104Gly missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.3331G>T p.Gly1111Trp missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.3475G>A p.Gly1159Arg missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.4465G>A p.Asp1489Asn missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.5596T>A p.Trp1866Arg missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.5598G>T p.Trp1866Cys missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.5647G>A p.Gly1883Arg missense_variant De novo NA Simplex 30827496 Cogn B , et al. (2019)
c.310G>A p.Glu104Lys missense_variant De novo NA Simplex 28263302 C Yuen RK , et al. (2017)
c.3316G>A p.Glu1106Lys missense_variant De novo NA Multiplex 30827496 Cogn B , et al. (2019)
c.3652G>A p.Ala1218Thr missense_variant De novo NA Simplex 28263302 C Yuen RK , et al. (2017)
c.1195G>A p.Val399Ile missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.5575C>T p.Arg1859Cys missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.11461C>T p.Arg3821Cys missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.3761C>A p.Ser1254Tyr missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.7090C>T p.Leu2364Phe missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.10775C>G p.Ser3592Cys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2575G>A p.Asp859Asn missense_variant Unknown - Multi-generational 30827496 Cogn B , et al. (2019)
c.5795C>T p.Pro1932Leu missense_variant Familial Maternal Multiplex 30827496 Cogn B , et al. (2019)
c.3316G>A p.Glu1106Lys missense_variant Unknown Not maternal Simplex 30827496 Cogn B , et al. (2019)
c.3111C>A p.Ser1037Arg missense_variant De novo NA Multi-generational 30827496 Cogn B , et al. (2019)
c.5647G>A p.Gly1883Arg missense_variant De novo NA Multi-generational 30827496 Cogn B , et al. (2019)
c.11270G>A p.Arg3757Gln missense_variant De novo NA Simplex 23934111 Epi4K Consortium , et al. (2013)
c.11270G>A p.Arg3757Gln missense_variant De novo NA Extended multiplex 30827496 Cogn B , et al. (2019)
c.3311A>G p.Glu1104Gly missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.3337G>A p.Val1113Met missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.4634C>T p.Ala1545Val missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.5596T>A p.Trp1866Arg missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.5598G>T p.Trp1866Cys missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.7697C>G p.Ala2566Gly missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.10096C>G p.His3366Asp missense_variant De novo NA - 28135719 Deciphering Developmental Disorders Study (2017)
c.7950_7951insAGATAAG p.Glu2651ArgfsTer2 frameshift_variant De novo NA Simplex 28263302 C Yuen RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Score Delta: Decreased from 4S to 3S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Reports Added
[New Scoring Scheme]
1/1/2019
icon
4S

Increased from to 4S

Description

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Krishnan Probability Score

Score 0.49167643518953

Ranking 5259/25841 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 1

Ranking 6/18225 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 0.999

Ranking 5/239 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 0.75043382725747

Ranking 1559/18665 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 0.4270510239026

Ranking 1152/20870 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.
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