TRIP11

protein-coding

thyroid hormone receptor interactor 11, the group of Golgins

Gene summary

This gene was identified based on the interaction of its protein product with thyroid hormone receptor beta. This protein is associated with the Golgi apparatus. The N-terminal region of the protein binds Golgi membranes and the C-terminal region binds the minus ends of microtubules; thus, the protein is thought to play a role in assembly and maintenance of the Golgi ribbon structure around the centrosome. Mutations in this gene cause achondrogenesis type IA.[provided by RefSeq, Mar 2010]

MANE transcript

NM_004239.4

Inheritance

ClinVar variants

P:94U:445B:250

Top phenotype

Achondrogenesis, type IA; Odontochondrodysplasia

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr14:91,965,991-92,040,896

External References & Databases

Ensembl (ENSG00000100815)

Transcript & Mutation Effects

hg38 • Region Span ~74.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

achondrogenesis type IAMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008701

Submitter: Ambry Genetics

TRIP11-related skeletal dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:1040009

Submitter: PanelApp Australia

achondrogenesis type IASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008701

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

achondrogenesis type IASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008701

Submitter: Orphanet

achondrogenesis type IASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008701

Submitter: Labcorp Genetics (formerly Invitae)

TRIP11-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1040009

Submitter: Ambry Genetics

TRIP11-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1040009

Submitter: ClinGen

TRIP11 (OMIM: 604505) was first reported in relation to autosomal recessive Achondrogensis type 1A (OMIM:200600) in 2010 (Smits et al., PMID: 20089971). Variants in TRIP11 have also been reported in individuals with autosomal recessive Odontochondrodysplasia (OMIM: 184260). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Some variants have been reported in both Odontochondrodysplasia and Achondrogenesis type 1A cases. Patients with either condition have affected Golgi apparatus. Odontochondrodysplasia is a milder form of Achondrogenesis type 1A with all patients to date being shown to have at least one hypomorphic variant by splicing/functional studies. Although the two condition are clinically distinct, the molecular causes of this difference cannot always be distinguished. Therefore, we decided to curate both these entities together under the term “TRIP11 related skeletal dysplasia”. At least 42 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. For the purposes of this curation, 16 variants in this gene were scored in the following 4 publications: PMIDs 23956106, 29620724, 29872333 30728324. More variant evidence is available in the literature, but the maximum score for variant evidence (12 pts.) has been reached. This gene-disease association is supported by mouse models (PMID 20089971) and expression studies (PMID 30728324). In summary, there is definitive evidence to support the relationship between TRIP11 and autosomal recessive TRIP11 related skeletal dysplasia. This 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 Prenatal Expert Panel on the 01/10/2024 (SOP Version 10).

achondrogenesis type IADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008701

Submitter: G2P

Clinical Genomic Database (CGD)

Achondrogenesis, type IA; OdontochondrodysplasiaAR

Manifestation: Dental; Musculoskeletal; Pulmonary; Renal

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

Refs: 4885523; 7460382; 3275766; 18241073; 20089971; 30728324

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRIP11 variants in ClinVar

11 Conditions Cataloged

Achondrogenesis, type IATotal: 635

not providedTotal: 240

Inborn genetic diseasesTotal: 219

not specifiedTotal: 79

Connective tissue disorderTotal: 44

TRIP11-related disorderTotal: 42

Odontochondrodysplasia 1Total: 34

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004239.4. 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			13 clinvar	188 clinvar	7 clinvar	208
missense		3 clinvar	423 clinvar	47 clinvar	8 clinvar	481
nonsense	24 clinvar	7 clinvar	1 clinvar			32
start loss						0
frameshift	35 clinvar	12 clinvar	1 clinvar			48
splice donor/acceptor (+/-2bp)	3 clinvar	10 clinvar	7 clinvar			20
Total	62	32	445	235	15	789

Highest pathogenic variant AF is 0.000095918906

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004239.4	RefSeq	NP_004230.2	21	MANE Select
ENST00000267622.8	Ensembl	ENSP00000267622.4	21	MANE Select
NM_001321851.1	RefSeq	NP_001308780.1	21	Standard
ENST00000554357.5	Ensembl	ENSP00000451032.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Intra-Golgi traffic
Intra-Golgi and retrograde Golgi-to-ER traffic
Intraflagellar transport

Biological Process

ventricular septum development
chondrocyte differentiation involved in endochondral bone morphogenesis
transcription by RNA polymerase II
protein glycosylation
Golgi organization

Molecular Function

transcription coactivator activity
protein binding

Cellular Component

Golgi membrane
inner acrosomal membrane
outer acrosomal membrane
nucleus
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000267622
Coding exons: 21
Length: 74906
Individuals with no LoFs: 125562
Homozygous LoFs: 0
Heterozygous LoFs: 186
Defined: 125748
p: 0.000740

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.515	903	948	0.953	0.0000464	13129
Missense (PolyPhen)		230	270.47	0.85036		4021
Synonymous	-0.886	367	346	1.06	0.0000175	3506
Loss of Function	5.72	39	101	0.386	0.00000554	1259

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.0016	0.0016	notable
European (Non-Finnish)	0.00090	0.00089	rare
South Asian	0.00053	0.00052	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds the ligand binding domain of the thyroid receptor (THRB) in the presence of triiodothyronine and enhances THRB- modulated transcription. Golgi auto-antigen; probably involved in maintaining cis-Golgi structure. {ECO:0000269|PubMed:10189370, ECO:0000269|PubMed:9256431}.;
Disease: DISEASE: Note=A chromosomal aberration involving TRIP11 may be a cause of acute myelogenous leukemia. Translocation t(5;14)(q33;q32) with PDGFRB. The fusion protein may be involved in clonal evolution of leukemia and eosinophilia. {ECO:0000269|PubMed:9373237}.; DISEASE: Achondrogenesis 1A (ACG1A) [MIM:200600]: A form of achondrogenesis type 1, a lethal form of chondrodysplasia characterized by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death. In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. {ECO:0000269|PubMed:20089971}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.900
RVIS EVS: 0.31
RVIS percentile EVS: 72.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.805

Gene Damage Prediction

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