TRIP4

Chr 15AR

thyroid hormone receptor interactor 4

Also known as: ASC-1, ASC1, HsT17391, MDCDC, SMABF1, ZC2HC5

NCBI Gene: 9325 ENSG00000103671 UniProt: Q15650 OMIM: 604501

This protein functions as a transcription coactivator that associates with nuclear receptors and basal transcription factors to facilitate gene transcription, and also plays a role in ribosome quality control during protein translation. Mutations cause spinal muscular atrophy with congenital bone fractures type 1 and congenital muscular dystrophy (Davignon-Chauveau type), both presenting in early infancy with severe muscle weakness and bone fragility. These conditions follow autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a subunit of the tetrameric nuclear activating signal cointegrator 1 (ASC-1) complex, which associates with transcriptional coactivators, nuclear receptors and basal transcription factors to facilitate nuclear receptors-mediated transcription. This protein is localized in the nucleus and contains an E1A-type zinc finger domain, which mediates interaction with transcriptional coactivators and ligand-bound nuclear receptors, such as thyroid hormone receptor and retinoid X receptor alpha, but not glucocorticoid receptor. Mutations in this gene are associated with spinal muscular atrophy with congenital bone fractures-1 (SMABF1). [provided by RefSeq, Apr 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.672 OMIM phenotypes

Clinical Summary— TRIP4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

37 unique Pathogenic / Likely Pathogenic· 139 VUS of 354 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.000

Z-score 3.18

OE 0.45 (0.30–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.57Z-score

OE missense 0.91 (0.82–1.00)

275 obs / 302.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.30–0.67)

0≤0.351.4

Missense OE?0.91 (0.82–1.00)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 17 / 38.2Missense obs/exp: 275 / 302.9Syn Z: -0.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTRIP4-related prenatal spinal muscular atrophy and congenital bone fracturesLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6454th %ile

GOF

0.4776th %ile

LOF

0.3454th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

354 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic15

VUS139

Likely Benign130

Benign31

Conflicting4

Pathogenic

Likely Pathogenic

139

VUS

130

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	1	2	0	22
Likely Pathogenic	12	0	3	0	15
VUS	4	134	1	0	139
Likely Benign	0	5	68	57	130
Benign	0	0	25	6	31
Conflicting	—				4
Total	35	140	99	63	341

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap TRIP4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →