TRIP4
protein-codingthyroid hormone receptor interactor 4, the group of Zinc fingers|Activating signal cointegrator 1 complex
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~67.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014806
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014896
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014806
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0000209
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014806
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014806
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TRIP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016213.5. 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 | 57 | 3 | 60 | |||
| missense | 1 | 132 | 9 | 142 | ||
| nonsense | 9 | 7 | 16 | |||
| start loss | 0 | |||||
| frameshift | 9 | 3 | 2 | 14 | ||
| splice donor/acceptor (+/-2bp) | 5 | 5 | 10 | |||
| Total | 19 | 15 | 139 | 66 | 3 | 242 |
Highest pathogenic variant AF is 0.0000489435
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057297.2 | 13 | MANE Select | |
| Ensembl | ENSP00000261884.3 | 13 | MANE Select | |
| RefSeq | NP_001308853.1 | 9 | Standard | |
| Ensembl | ENSP00000452764.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| trip4 | Danio rerio | Structure: motor neuron Quality: branchiness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of transcription, DNA-templated
- intracellular estrogen receptor signaling pathway
- regulation of myoblast differentiation
- positive regulation of transcription, DNA-templated
- toxin transport
Molecular Function
- protease binding
- transcription coactivator activity
- protein binding
- zinc ion binding
- nuclear receptor binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- centrosome
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261884
- Coding exons
- 13
- Length
- 67556
- Individuals with no LoFs
- 125680
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 68
- Defined
- 125748
- p
- 0.000270
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.569 | 275 | 303 | 0.908 | 0.0000154 | 3789 |
| Missense (PolyPhen) | 85 | 105.16 | 0.80829 | 1294 | ||
| Synonymous | -0.373 | 114 | 109 | 1.05 | 0.00000535 | 1077 |
| Loss of Function | 3.18 | 17 | 38.2 | 0.445 | 0.00000227 | 412 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00056 | 0.00055 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0011 | 0.0011 | notable |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00019 | 0.00018 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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 (PubMed:10454579, PubMed:25219498). Also involved in androgen receptor transactivation (By similarity). 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 (PubMed:12077347). May play a role in the development of neuromuscular junction (PubMed:26924529). May play a role in late myogenic differentiation (By similarity). {ECO:0000250|UniProtKB:Q9QXN3, ECO:0000269|PubMed:10454579, ECO:0000269|PubMed:12077347, ECO:0000269|PubMed:25219498, ECO:0000269|PubMed:26924529}.;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:26924529}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:27008887}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.101
Intolerance Scores
- LoFtool
- 0.214
- RVIS EVS
- -1.02
- RVIS percentile EVS
- 8.04
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.989
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |