TRIP4

Summary

TRIP4 (thyroid hormone receptor interactor 4, HGNC:12310) is a protein-coding gene on chromosome 15q22.31, encoding Activating signal cointegrator 1 (Q15650). Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription.

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).

Source: NCBI Gene 9325 — RefSeq curated summary.

At a glance

• Gene–disease (curated): prenatal-onset spinal muscular atrophy with congenital bone fractures (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 330 total — 22 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 69
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016213

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12310
Approved symbol	TRIP4
Name	thyroid hormone receptor interactor 4
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	HsT17391, ZC2HC5, ASC-1
Ensembl gene	ENSG00000103671
Ensembl biotype	protein_coding
OMIM	604501
Entrez	9325

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 12 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000261884, ENST00000557834, ENST00000558162, ENST00000558442, ENST00000558820, ENST00000559565, ENST00000559777, ENST00000559833, ENST00000560475, ENST00000560567, ENST00000560920, ENST00000561265, ENST00000907326, ENST00000907327, ENST00000907328, ENST00000907329, ENST00000935228, ENST00000935229, ENST00000935230, ENST00000949915, ENST00000949916

RefSeq mRNA: 2 — MANE Select: NM_016213 NM_001321924, NM_016213

CCDS: CCDS10194

Canonical transcript exons

ENST00000261884 — 13 exons

Exon	Start	End
ENSE00000943039	64424031	64424155
ENSE00001106804	64409613	64409828
ENSE00001201431	64425540	64425631
ENSE00001252538	64414085	64414211
ENSE00001252564	64387836	64387964
ENSE00003500804	64395398	64395531
ENSE00003571933	64445006	64445108
ENSE00003589989	64454997	64455303
ENSE00003620859	64393946	64394115
ENSE00003633136	64406330	64406459
ENSE00003650492	64397606	64397818
ENSE00003655234	64400743	64400821
ENSE00003673032	64418541	64418728

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 93.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9679 / max 155.1186, expressed in 1743 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147174	14.6792	1742
207564	0.2478	88
147175	0.0409	16

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	93.16	gold quality
lower esophagus mucosa	UBERON:0035834	92.94	gold quality
amniotic fluid	UBERON:0000173	92.50	gold quality
mucosa of transverse colon	UBERON:0004991	92.44	gold quality
jejunal mucosa	UBERON:0000399	91.70	gold quality
monocyte	CL:0000576	91.27	gold quality
mononuclear cell	CL:0000842	91.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.02	gold quality
leukocyte	CL:0000738	91.02	gold quality
right lobe of thyroid gland	UBERON:0001119	90.38	gold quality
esophagus squamous epithelium	UBERON:0006920	90.26	gold quality
left lobe of thyroid gland	UBERON:0001120	90.08	gold quality
thyroid gland	UBERON:0002046	89.99	gold quality
cortical plate	UBERON:0005343	89.84	gold quality
ganglionic eminence	UBERON:0004023	89.76	gold quality
adenohypophysis	UBERON:0002196	88.86	gold quality
esophagus mucosa	UBERON:0002469	88.80	gold quality
metanephros cortex	UBERON:0010533	88.80	gold quality
granulocyte	CL:0000094	88.68	gold quality
rectum	UBERON:0001052	88.65	gold quality
cortex of kidney	UBERON:0001225	88.63	gold quality
renal glomerulus	UBERON:0000074	88.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.51	gold quality
epithelium of esophagus	UBERON:0001976	88.45	gold quality
tibial artery	UBERON:0007610	88.36	gold quality
popliteal artery	UBERON:0002250	88.35	gold quality
palpebral conjunctiva	UBERON:0001812	88.32	gold quality
islet of Langerhans	UBERON:0000006	88.27	gold quality
nephron tubule	UBERON:0001231	88.17	gold quality
skin of leg	UBERON:0001511	88.17	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting TRIP4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-138-1-3P	98.25	67.89	867
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-148B-5P	97.29	66.30	992
HSA-MIR-6874-3P	97.29	66.34	975
HSA-MIR-6816-3P	95.05	66.08	459

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1. (PMID:19074642)
• GWAS in a large Spanish sample identifies TRIP4 (rs74615166) as a significant locus for Alzheimer’s disease risk. (PMID:24495969)
• Reports reveal the first TRIP4 mutation defining a novel form of congenital muscle disease and establish the importance of ASC-1 in human skeletal muscle, identify transcriptional co-regulation as novel pathophysiological pathway, define ASC-1 as a regulator of late myogenic differentiation and suggest defects in myotube growth as a novel myopathic mechanism. (PMID:27008887)
• Study showed that TRIP4 promoted melanoma growth through modulation of COX-2 and iNOS expression partially by activating NF-kappaB signaling indirectly and partially by the direct anchoring of itself at COX-2 and iNOS promoter via synergy with p300. Clinical data showed that high expression of TRIP4 was positively correlated with increased expression of COX-2 and iNOS and predicted poor prognosis in melanoma patients. (PMID:28899685)
• TRIP4 promotes tumor growth and metastasis and regulates radiosensitivity of cervical cancer by activating MAPK, PI3K/AKT, and hTERT signaling. (PMID:30905820)
• results expand the spectrum of TRIP4-associated disease to include mild adult forms, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation. (PMID:31794073)
• MicroRNA-518-3p suppresses cell proliferation, invasiveness, and migration in colorectal cancer via targeting TRIP4. (PMID:32298598)
• Inherited Defects of the ASC-1 Complex in Congenital Neuromuscular Diseases. (PMID:34204919)
• ASC1 complex related conditions: Two novel paediatric patients with TRIP4 pathogenic variants and review of literature. (PMID:35276412)
• LINC00668 promoted non-small lung cancer progression by miR-518c-3p/TRIP4 axis. (PMID:37718780)
• Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter. (PMID:38582862)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	trip4	ENSDARG00000098074
mus_musculus	Trip4	ENSMUSG00000032386
rattus_norvegicus	Trip4	ENSRNOG00000016121
drosophila_melanogaster	CG11710	FBGN0031115
caenorhabditis_elegans		WBGENE00000208

Protein

Protein identifiers

Activating signal cointegrator 1 — Q15650 (reviewed: Q15650)

Alternative names: Thyroid receptor-interacting protein 4

All UniProt accessions (6): Q15650, H0YK63, H0YKD9, H0YL91, H0YLN7, H3BMU9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription. May thereby play an important role in establishing distinct coactivator complexes under different cellular conditions. Plays a role in thyroid hormone receptor and estrogen receptor transactivation. Also involved in androgen receptor transactivation. Plays a pivotal role in the transactivation of NF-kappa-B, SRF and AP1. Acts as a mediator of transrepression between nuclear receptor and either AP1 or NF-kappa-B. May play a role in the development of neuromuscular junction. May play a role in late myogenic differentiation. Also functions as part of the RQC trigger (RQT) complex that activates the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation.

Subunit / interactions. Interacts with the thyroid hormone receptor/TR (via the ligand-binding domain); this interaction requires the presence of thyroid hormone. Interacts with the androgen receptor/AR; in an androgen, testosterone and dihydrotestosterone-dependent manner. Interacts with ESR1 (estrogen ligand-bound); competes with UFSP2. Interacts with UFSP2; competes with ligand-bound ESR1. Interacts with DDRGK1 and UFL1; the interaction with DDRGK1 is direct. Interacts with NCOA1. Interacts with EP300. Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3. Identified in the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4. Interacts with NEK6. Interacts with CSRP1. Interacts with ZCCHC4.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Phosphorylated by NEK6. Polyufmylated by the UFM1-conjugating system composed of the enzymes UBA5, UFC1 and UFL1. Deufmylated by the protease UFSP2. Ufmylation of TRIP4 is promoted by ligand-bound nuclear receptors that compete with UFSP2 for interaction with TRIP4. Nuclear receptors-induced ufmylation promotes the recruitment of additional transcriptional coactivators like EP300 and NCOA1 and therefore the assembly of a coactivator complex facilitating nuclear receptor-mediated transcription.

Disease relevance. Spinal muscular atrophy with congenital bone fractures 1 (SMABF1) [MIM:616866] An autosomal recessive neuromuscular disorder characterized by prenatal-onset spinal muscular atrophy, multiple congenital contractures consistent with arthrogryposis multiplex congenita, respiratory distress, and congenital bone fractures. The disease is caused by variants affecting the gene represented in this entry. Muscular dystrophy, congenital, Davignon-Chauveau type (MDCDC) [MIM:617066] An autosomal recessive, severe congenital muscular dystrophy characterized by neonatal onset of muscle weakness predominantly involving axial muscles, life-threatening respiratory failure, skin abnormalities and joint hyperlaxity without contractures. Muscle biopsies show multi-minicores, caps and dystrophic lesions. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C4-type zinc finger mediates a competitive interaction with UFSP2 and ligand-bound nuclear receptors. It also mediates interaction with the transcriptional coactivators and the basal transcription machinery.

RefSeq proteins (2): NP_001308853, NP_057297* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007374	ASCH_domain	Domain
IPR009349	TRIP4/RQT4_C2HC5_Znf	Domain
IPR015947	PUA-like_sf	Homologous_superfamily
IPR039128	TRIP4-like	Family
IPR056993	TRIP4_3rd_dom	Domain
IPR056994	TRI4_N	Domain

Pfam: PF04266, PF06221, PF23134, PF23135

UniProt features (38 total): helix 9, strand 8, modified residue 4, cross-link 4, sequence conflict 3, turn 3, region of interest 3, initiator methionine 1, chain 1, domain 1, zinc finger region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9KYK	X-RAY DIFFRACTION	1.02
8YFJ	X-RAY DIFFRACTION	1.84
8YEW	X-RAY DIFFRACTION	1.9
8YEY	X-RAY DIFFRACTION	2
8YFI	X-RAY DIFFRACTION	2.02
8YXW	X-RAY DIFFRACTION	2.1
9KYL	X-RAY DIFFRACTION	2.15
8YXX	X-RAY DIFFRACTION	2.65
8ALZ	ELECTRON MICROSCOPY	3.4
2E5O	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15650-F1	71.54	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 341, 324, 325, 334, 367, 2, 276, 289

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9954716	ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA

MSigDB gene sets: 362 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPID, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CAGCTG_AP4_Q5, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_TRANSLATION, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, HEN1_01

GO Biological Process (7): regulation of DNA-templated transcription (GO:0006355), estrogen receptor signaling pathway (GO:0030520), ribosome disassembly (GO:0032790), regulation of myoblast differentiation (GO:0045661), positive regulation of DNA-templated transcription (GO:0045893), rescue of stalled cytosolic ribosome (GO:0072344), ribosome-associated ubiquitin-dependent protein catabolic process (GO:1990116)

GO Molecular Function (10): protease binding (GO:0002020), transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), nuclear receptor binding (GO:0016922), protein kinase binding (GO:0019901), nuclear estrogen receptor binding (GO:0030331), histone acetyltransferase binding (GO:0035035), ubiquitin-like protein ligase binding (GO:0044389), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), nuclear body (GO:0016604), neuromuscular junction (GO:0031594), protein-containing complex (GO:0032991), RQC-trigger complex (GO:0180022), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
enzyme binding	3
cellular anatomical structure	3
DNA-templated transcription	2
intracellular membraneless organelle	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nuclear receptor-mediated steroid hormone signaling pathway	1
organelle disassembly	1
myoblast differentiation	1
regulation of cell differentiation	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cytoplasmic translational elongation	1
ribosome disassembly	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
transition metal ion binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
kinase binding	1
nuclear receptor binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
nucleoplasm	1
synapse	1
cellular_component	1
protein-containing complex	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIP4	ASCC3	Q8N3C0	969
TRIP4	ASCC2	Q9H1I8	969
TRIP4	ASCC1	Q8N9N2	897
TRIP4	TBP	P20226	701
TRIP4	TXNRD2	Q9NNW7	654
TRIP4	UFSP2	Q9NUQ7	634
TRIP4	ZNF598	Q86UK7	605
TRIP4	THRB	P10828	592
TRIP4	UFL1	O94874	574
TRIP4	NEMF	O60524	558
TRIP4	UFM1	P61960	549
TRIP4	ALKBH3	Q96Q83	536
TRIP4	NCOA1	Q15788	531
TRIP4	PHB2	Q99623	531
TRIP4	DDRGK1	Q96HY6	507

IntAct

63 interactions, top by confidence:

A	B	Type	Score
ASCC2	TRIP4	psi-mi:“MI:0914”(association)	0.640
RACK1	RIOK3	psi-mi:“MI:0914”(association)	0.640
ALKBH3	INPPL1	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
TRIP4	ASCC3	psi-mi:“MI:0914”(association)	0.530
ALKBH3	TRIP4	psi-mi:“MI:0914”(association)	0.530
ASCC1	TRIP4	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	TRIP4	psi-mi:“MI:0915”(physical association)	0.370
PAX9	TRIP4	psi-mi:“MI:0915”(physical association)	0.370
NR2F2	TRIP4	psi-mi:“MI:0915”(physical association)	0.370
XBP1	TRIP4	psi-mi:“MI:0915”(physical association)	0.370
TRIP4	RELA	psi-mi:“MI:0915”(physical association)	0.370
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
KIF11	ILVBL	psi-mi:“MI:0914”(association)	0.350
Srp72		psi-mi:“MI:0914”(association)	0.350
Junb	RGPD3	psi-mi:“MI:0914”(association)	0.350
CDT1	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
BCAR1	MYO1C	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ASCC1	IGLL5	psi-mi:“MI:0914”(association)	0.350
rep	STXBP3	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350

BioGRID (276): TRIP4 (Affinity Capture-MS), TRIP4 (Protein-peptide), TRIP4 (Affinity Capture-MS), TRIP4 (Affinity Capture-MS), TRIP4 (Affinity Capture-MS), TRIP4 (Co-fractionation), TRIP4 (Reconstituted Complex), RXRA (Two-hybrid), THRB (Two-hybrid), TRIP4 (Reconstituted Complex), TRIP4 (Reconstituted Complex), TRIP4 (Reconstituted Complex), TRIP4 (Reconstituted Complex), TRIP4 (Reconstituted Complex), NFKB1 (Reconstituted Complex)

ESM2 similar proteins: A0JN62, A2RT67, A2RUS2, A2VDU2, A4IFB6, A4IIM3, A7MBL8, B1H2P5, B4F779, O94967, P48553, Q08CL8, Q0VEJ0, Q14161, Q15650, Q3TLI0, Q4R350, Q5RAQ5, Q5RCP7, Q5RDV5, Q5TKA1, Q5XIA4, Q5ZIW2, Q5ZJK1, Q68CZ1, Q6AYF1, Q6QD73, Q7TSG1, Q7ZYH1, Q8BH15, Q8BIK4, Q8BKH7, Q8C735, Q8CG73, Q8CGF6, Q8IWR0, Q8IZQ1, Q8N6S4, Q8N960, Q8NEU8

Diamond homologs: O13855, Q15650, Q9QXN3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the ternary complex, and subsequently, the 43S complex	9	36.6×	2e-10
Translation initiation complex formation	10	35.9×	2e-11
Ribosomal scanning and start codon recognition	10	35.9×	2e-11
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	7	35.9×	3e-08
Eukaryotic Translation Initiation	6	34.9×	4e-07
Cap-dependent Translation Initiation	6	34.9×	4e-07
SARS-CoV-1 modulates host translation machinery	6	34.9×	4e-07
Eukaryotic Translation Elongation	6	31.5×	7e-07

GO biological processes:

GO term	Partners	Fold	FDR
translational initiation	6	33.1×	5e-06
ribosomal small subunit biogenesis	8	28.0×	2e-07
cytoplasmic translation	8	22.8×	6e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

330 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	10
Uncertain significance	133
Likely benign	115
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1694758	NM_016213.5(TRIP4):c.890G>A (p.Trp297Ter)	Pathogenic
1801722	NM_016213.5(TRIP4):c.265A>T (p.Lys89Ter)	Pathogenic
1934244	NM_016213.5(TRIP4):c.135dup (p.Arg46fs)	Pathogenic
1953971	NM_016213.5(TRIP4):c.1261C>T (p.Arg421Ter)	Pathogenic
2002769	NM_016213.5(TRIP4):c.422del (p.Asn141fs)	Pathogenic
2122425	NM_016213.5(TRIP4):c.472C>T (p.Gln158Ter)	Pathogenic
224632	NM_016213.5(TRIP4):c.832C>T (p.Arg278Ter)	Pathogenic
2426282	NC_000015.9:g.(?64680063)(64680183_?)del	Pathogenic
253117	NM_016213.5(TRIP4):c.950G>A (p.Arg317Gln)	Pathogenic
2715719	NM_016213.5(TRIP4):c.59T>A (p.Leu20Ter)	Pathogenic
2751750	NM_016213.5(TRIP4):c.160C>T (p.Gln54Ter)	Pathogenic
2858605	NM_016213.5(TRIP4):c.1402del (p.Trp468fs)	Pathogenic
2907549	NM_016213.5(TRIP4):c.136C>T (p.Arg46Ter)	Pathogenic
3027261	NM_016213.5(TRIP4):c.831dup (p.Arg278fs)	Pathogenic
3233246	NM_016213.5(TRIP4):c.55_56insCT (p.Gln19fs)	Pathogenic
3233247	NM_016213.5(TRIP4):c.1199del (p.Gln400fs)	Pathogenic
3385340	NM_016213.5(TRIP4):c.239C>A (p.Ser80Ter)	Pathogenic
3621461	NM_016213.5(TRIP4):c.949C>T (p.Arg317Ter)	Pathogenic
4690706	NM_016213.5(TRIP4):c.1460_1463dup (p.Arg489fs)	Pathogenic
4847879	NC_000015.9:g.(?64680034)(64747503_?)del	Pathogenic
818010	NM_016213.5(TRIP4):c.779del (p.Glu260fs)	Pathogenic
961908	NM_016213.5(TRIP4):c.462_463del (p.Glu156fs)	Pathogenic
1300156	NM_016213.4:c.1359_1575del	Likely pathogenic
1300157	NM_016213.5(TRIP4):c.1255C>T (p.Gln419Ter)	Likely pathogenic
1494475	NM_016213.5(TRIP4):c.1484-2A>C	Likely pathogenic
2445842	NC_000015.9:g.(?64680002)(64680164_64686144)del	Likely pathogenic
2581351	NM_016213.5(TRIP4):c.272-1G>T	Likely pathogenic
2778895	NM_016213.5(TRIP4):c.827+1G>T	Likely pathogenic
3243891	NC_000015.9:g.(?64701792)(64706430_?)dup	Likely pathogenic
3775196	NM_016213.5(TRIP4):c.886C>T (p.Gln296Ter)	Likely pathogenic

SpliceAI

2296 predictions. Top by Δscore:

Variant	Effect	Δscore
15:64387965:G:GG	donor_gain	1.0000
15:64387991:G:GT	donor_gain	1.0000
15:64387991:G:T	donor_gain	1.0000
15:64388004:G:GT	donor_gain	1.0000
15:64388004:G:T	donor_gain	1.0000
15:64388029:G:GT	donor_gain	1.0000
15:64388029:G:T	donor_gain	1.0000
15:64388050:T:G	donor_gain	1.0000
15:64393942:T:A	acceptor_gain	1.0000
15:64394111:AGATG:A	donor_gain	1.0000
15:64394112:GATG:G	donor_gain	1.0000
15:64394112:GATGG:G	donor_gain	1.0000
15:64394113:ATG:A	donor_gain	1.0000
15:64394114:TG:T	donor_gain	1.0000
15:64394114:TGG:T	donor_loss	1.0000
15:64394115:GG:G	donor_gain	1.0000
15:64394115:GGTA:G	donor_loss	1.0000
15:64394116:G:GA	donor_loss	1.0000
15:64394116:G:GG	donor_gain	1.0000
15:64394116:GT:G	donor_gain	1.0000
15:64394117:T:G	donor_loss	1.0000
15:64397600:C:G	acceptor_gain	1.0000
15:64397816:CTGG:C	donor_loss	1.0000
15:64397817:TGGT:T	donor_loss	1.0000
15:64397818:GGT:G	donor_loss	1.0000
15:64397819:G:A	donor_loss	1.0000
15:64397820:T:G	donor_loss	1.0000
15:64400832:GTCTT:G	donor_gain	1.0000
15:64406329:GGA:G	acceptor_gain	1.0000
15:64406396:T:G	donor_gain	1.0000

AlphaMissense

3811 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:64397774:T:C	C192R	1.000
15:64424074:T:A	W468R	1.000
15:64424074:T:C	W468R	1.000
15:64397711:T:C	C171R	0.999
15:64397712:G:A	C171Y	0.999
15:64397717:T:C	C173R	0.999
15:64397750:T:C	C184R	0.999
15:64397752:T:G	C184W	0.999
15:64397759:T:C	C187R	0.999
15:64397766:G:C	R189P	0.999
15:64397774:T:A	C192S	0.999
15:64397775:G:A	C192Y	0.999
15:64397775:G:C	C192S	0.999
15:64397776:T:G	C192W	0.999
15:64397798:T:C	C200R	0.999
15:64397800:C:G	C200W	0.999
15:64406438:T:C	L269P	0.999
15:64425576:T:C	L507P	0.999
15:64397711:T:A	C171S	0.998
15:64397712:G:C	C171S	0.998
15:64397713:T:G	C171W	0.998
15:64397719:C:G	C173W	0.998
15:64397750:T:A	C184S	0.998
15:64397751:G:C	C184S	0.998
15:64397760:G:A	C187Y	0.998
15:64397772:T:A	V191D	0.998
15:64397775:G:T	C192F	0.998
15:64397793:G:A	G198D	0.998
15:64397798:T:A	C200S	0.998
15:64397799:G:A	C200Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000003557 (15:64436516 A>T), RS1000015332 (15:64429672 T>C), RS1000118891 (15:64423344 TC>T), RS1000160908 (15:64430144 C>T), RS1000173813 (15:64405852 C>G), RS1000197666 (15:64413279 C>T), RS1000220255 (15:64389473 A>G), RS1000259662 (15:64450436 A>G), RS1000268737 (15:64406319 T>A,C), RS1000295815 (15:64400923 T>A), RS1000311837 (15:64449486 T>C), RS1000373403 (15:64442639 A>G), RS1000461643 (15:64437018 C>G,T), RS1000473132 (15:64388802 C>G,T), RS1000492549 (15:64423675 A>G)

Disease associations

OMIM: gene MIM:604501 | disease phenotypes: MIM:617066, MIM:271225, MIM:616866, MIM:160150

GenCC curated gene-disease

Disease	Classification	Inheritance
prenatal-onset spinal muscular atrophy with congenital bone fractures	Strong	Autosomal recessive
spinal muscular atrophy with congenital bone fractures 1	Strong	Autosomal recessive
congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome	Strong	Autosomal recessive

Mondo (4): congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome (MONDO:0014896), spinal muscular atrophy with congenital bone fractures 1 (MONDO:0014806), centronuclear myopathy (MONDO:0018947), prenatal-onset spinal muscular atrophy with congenital bone fractures (MONDO:0000209)

Orphanet (2): Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome (Orphanet:486815), Centronuclear myopathy (Orphanet:595)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000467	Neck muscle weakness
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000823	Delayed puberty
HP:0000958	Dry skin
HP:0000966	Hypohidrosis
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001558	Decreased fetal movement
HP:0001562	Oligohydramnios
HP:0001612	Weak cry
HP:0001622	Premature birth
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001643	Patent ductus arteriosus
HP:0001655	Patent foramen ovale
HP:0001684	Secundum atrial septal defect
HP:0002015	Dysphagia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002245_31	Alzheimer’s disease (late onset)	4.000000e-07
GCST005232_36	Neuroticism	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564805	Spinal Muscular Atrophy, Type I, with Congenital Bone Fractures (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol AF	affects binding, affects folding, increases reaction, decreases reaction	2
Air Pollutants	decreases expression, increases abundance	2
Cyclosporine	increases expression	2
dicrotophos	decreases expression	1
bisphenol A	affects binding, affects folding, increases reaction	1
sodium arsenite	increases expression	1
sulindac sulfide	increases expression	1
potassium chromate(VI)	decreases expression	1
K 7174	increases expression	1
abrine	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Coal	decreases expression, increases abundance	1
Estradiol	affects binding, increases reaction	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	increases abundance, decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	increases methylation	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0S9	Ubigene HeLa TRIP4 KO	Cancer cell line	Female
CVCL_TU65	HAP1 TRIP4 (-) 1	Cancer cell line	Male
CVCL_XU74	HAP1 TRIP4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

12 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04033159	PHASE1/PHASE2	TERMINATED	Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies
NCT04743557	PHASE1/PHASE2	WITHDRAWN	Early Phase Human Drug Trial to Investigate DYN101 in Participants 2 to 17 Years With Centronuclear Myopathies
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT03351270	Not specified	COMPLETED	Prospective Natural History Study of Patients With Myotubular Myopathy and Other CentroNuclear Myopathies
NCT04064307	Not specified	RECRUITING	Myotubular and Centronuclear Myopathy Patient Registry
NCT04977648	Not specified	WITHDRAWN	Natural History Study of Patients With Centronuclear Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT05982119	Not specified	RECRUITING	Assessments in Patients With Muscular Pathology and in Control Subjects : The ActiLiège Next Study
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT07021820	Not specified	RECRUITING	Multispectral Optoacoustic Tomography for Advanced Imaging of Centronuclear Myopathy
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease