TRRAP

protein-coding

transformation/transcription domain associated protein, the group of SAGA complex|Tip60/Nua4 histone acetyltransferase complex subunits|Armadillo like helical domain containing|MicroRNA protein coding host genes

Gene summary

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. Deregulation of this gene may play a role in several types of cancer including glioblastoma multiforme. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

MANE transcript

NM_001375524.1

Inheritance

ClinVar variants

P:40U:1220B:915

Top phenotype

Developmental delay with or without dysmorphic facies and autism

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr7:98,877,933-99,050,831

External References & Databases

Ensembl (ENSG00000196367)

Transcript & Mutation Effects

hg38 • Region Span ~172.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorder with or without congenital anomaliesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100465

Submitter: ClinGen

The *TRRAP* gene is located on chromosome 7 at 7q22.1 and encodes the transformation/transcription domain associated protein, which functions as a cofactor to mediate histone acetylation and also plays a role in DNA damage repair. *TRRAP* was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies in 2012 (Xu et al., PMID: 23042115). This variable disorder can include developmental delay, intellectual disability, seizures, psychiatric disorders, characteristic dysmorphism, and in some cases, malformations or anomalies of other body systems. More than 30 cases have been described, almost exclusively with missense variants, the majority of which were shown to have occurred *de novo* (PMIDs: 23042115, 28628100, 28392909, 30424743, 30827496). At least one case of parental mosaicism has been reported. Twenty-four unique missense variants reported in 24 individuals from three publications were included in this curation (PMIDs: 23042115, 30424743, 30827496). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of disease has not yet been clearly delineated, although a gain of function or dominant-negative mechanism has been proposed. (PMID: 24792116). This gene-disease relationship is also supported by experimental evidence. In a mouse model, Nestin-cre driven neural-cell-specific conditional knockout results in microcephaly, premature differentiation of neural progenitors, depletion of progenitor pools, and reduced cortical thickness (PMID: 24792116); traditional gene knockout is embryonic lethal (PMID: 11544477). CRISPR-mediated disruption of *TRRAP* in zebrafish also results in developmental abnormalities that cannot be easily related to the human phenotype (PMIDs: 31231791, 34934055). In summary, there is definitive evidence supporting the relationship between *TRRAP* and autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 19, 2022.

developmental delay with or without dysmorphic facies and autismMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032760

Submitter: Ambry Genetics

hearing loss, autosomal dominant 75LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032911

Submitter: Ambry Genetics

developmental delay with or without dysmorphic facies and autismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032760

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay with or without dysmorphic facies and autismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032760

Submitter: PanelApp Australia

hearing loss, autosomal dominant 75LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032911

Submitter: PanelApp Australia

developmental delay with or without dysmorphic facies and autismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032760

Submitter: G2P

developmental delay with or without dysmorphic facies and autismDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032760

Submitter: Illumina

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental delay with or without dysmorphic facies and autismAD

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 23042115; 30424743; 31231791

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRRAP variants in ClinVar

16 Conditions Cataloged

not providedTotal: 2239

Inborn genetic diseasesTotal: 363

TRRAP-related disorderTotal: 229

not specifiedTotal: 222

Developmental delay with or without dysmorphic facies and autismTotal: 159

Hearing loss, autosomal dominant 75Total: 32

See casesTotal: 10

Complex neurodevelopmental disorder with or without congenital anomaliesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001375524.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			21 clinvar	701 clinvar	30 clinvar	752
missense	7 clinvar	27 clinvar	1154 clinvar	160 clinvar	23 clinvar	1371
nonsense		4 clinvar	16 clinvar			20
start loss						0
frameshift		1 clinvar	13 clinvar			14
splice donor/acceptor (+/-2bp)		1 clinvar	16 clinvar	1 clinvar		18
Total	7	33	1220	862	53	2175

Highest pathogenic variant AF is 0.0000065720296

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001375524.1	RefSeq	NP_001362453.1	72	MANE Select
ENST00000456197.2	Ensembl	ENSP00000394645.2	72	MANE Select
NM_001244580.2	RefSeq	NP_001231509.1	71	Standard
NM_003496.4	RefSeq	NP_003487.1	70	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HTLV-I infection - Homo sapiens (human)
Signaling by WNT
Signal Transduction
multi-step regulation of transcription by pitx2
Post-translational protein modification

Biological Process

DNA repair
regulation of transcription, DNA-templated
histone acetylation
histone deubiquitination
protein deubiquitination

Molecular Function

transcription coregulator activity
protein binding
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

SAGA complex
PCAF complex
Swr1 complex
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359863
Coding exons: 71
Length: 135311
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125747
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	8.17	1191	2.29e+3	0.520	0.000147	25405
Missense (PolyPhen)		200	647.77	0.30875		7151
Synonymous	-2.45	1038	942	1.10	0.0000674	7531
Loss of Function	12.6	6	197	0.0305	0.0000106	2182

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00022	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein, which is found in various multiprotein chromatin complexes with histone acetyltransferase activity (HAT), which gives a specific tag for epigenetic transcription activation. Component of the NuA4 histone acetyltransferase complex which is responsible for acetylation of nucleosomal histones H4 and H2A. Plays a central role in MYC transcription activation, and also participates in cell transformation by MYC. Required for p53/TP53-, E2F1- and E2F4-mediated transcription activation. Also involved in transcription activation mediated by the adenovirus E1A, a viral oncoprotein that deregulates transcription of key genes. Probably acts by linking transcription factors such as E1A, MYC or E2F1 to HAT complexes such as STAGA thereby allowing transcription activation. Probably not required in the steps following histone acetylation in processes of transcription activation. May be required for the mitotic checkpoint and normal cell cycle progression. Component of a SWR1- like complex that specifically mediates the removal of histone H2A.Z/H2AFZ from the nucleosome. {ECO:0000269|PubMed:11418595, ECO:0000269|PubMed:12138177, ECO:0000269|PubMed:12660246, ECO:0000269|PubMed:12743606, ECO:0000269|PubMed:14966270, ECO:0000269|PubMed:17967892, ECO:0000269|PubMed:24463511, ECO:0000269|PubMed:9708738}.;
Disease: DISEASE: Note=TRRAP mutation Phe-722 has been frequently found in cutaneous malignant melanoma, suggesting that TRRAP may play a role in the pathogenesis of melanoma. {ECO:0000269|PubMed:21499247}.;

Recessive Scores

pRec: 0.527

Intolerance Scores

LoFtool: 0.0406
RVIS EVS: -6.14
RVIS percentile EVS: 0.04

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.862

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium