TRRAP

Chr 7AD

transformation/transcription domain associated protein

Also known as: DEDDFA, DFNA75, PAF350/400, PAF400, STAF40, TR-AP, Tra1

NCBI Gene: 8295 ENSG00000196367 UniProt: Q9Y4A5 OMIM: 603015

The encoded protein is an adapter protein that recruits histone acetyltransferase complexes to chromatin for transcription activation and is required for MYC-, p53-, and E2F-mediated gene expression. Mutations cause autosomal dominant developmental delay with or without dysmorphic features and autism, as well as autosomal dominant deafness. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.06), indicating that heterozygous loss is likely pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.062 OMIM phenotypes

Clinical Summary— TRRAP

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder with or without congenital anomalies · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 92 VUS of 200 total submissions

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GeneReview available — TRRAP

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.06LOEUF

pLI 1.000

Z-score 12.59

OE 0.03 (0.02–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

8.17Z-score

OE missense 0.52 (0.49–0.55)

1191 obs / 2292.1 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.03 (0.02–0.06)

0≤0.351.4

Missense OE0.52 (0.49–0.55)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 6 / 196.5Missense obs/exp: 1191 / 2292.1Syn Z: -2.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTRRAP-related autism and syndromic intellectual disabilityOTHERAD

0.3196th %ile

GOF

0.2597th %ile

LOF

0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.06

DN1 literature citation

Literature Evidence

DNConsistent with the dominant negative effect, the stable expression of an N-terminal p400 fragment showed a decrease in the association of p400 with ATM, but did not alter the association of p400 with TRRAP.PMID:27814680

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.