TRIT1

protein-coding

tRNA isopentenyltransferase 1

Gene summary

This gene encodes a protein that that is targeted to the mitochondrion and modifies transfer RNAs (tRNAs) by adding a dimethylallyl group onto the adenine at position 37. This modification is important for maintaining the correct reading frame during protein translation. This gene is considered a tumor suppressor and its expression can decrease cell growth. Alternative splicing results in multiple transcripts variants, most of which are likely non-functional. [provided by RefSeq, Aug 2015]

MANE transcript

NM_017646.6

Inheritance

ClinVar variants

P:22U:94B:29

Top phenotype

Combined oxidative phosphorylation deficiency 35

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr1:39,838,110-39,883,511

External References & Databases

Ensembl (ENSG00000043514)

Transcript & Mutation Effects

hg38 • Region Span ~45.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation deficiency 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054742

Submitter: PanelApp Australia

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TRIT1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 13, 2022. The *TRIT1* gene encodes tRNA isopentenyltransferase 1, which catalyzes the transfer of an isopentyl group from dimethylallyl pyrophosphate onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs that bind to codons containing uridine. Of note, modifications of cytosolic tRNAs and mitochondrial tRNAs (mt-tRNAs) occur at nucleotide positions 34 and 37 in the anticodon loop. This promotes translational fidelity and efficiency by optimizing codon-anticodon fit within the ribosome. The *TRIT1* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24901367). While various names have been given to the constellation of features seen in those with *TRIT1*-related disease (including combined oxidative phosphorylation deficiency 35), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TRIT1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 15 variants (nine missense, two frameshift, three stop-gained, and one intronic) identified in ten probands from eight publications (PMIDs: 24901367, 28185376, 30977854, 31140736, 32088416, 32948376, 35568357, 35418828). Age of onset was typically in the first year of life. Features included infantile/early childhood onset epilepsy, global developmental delay, variable intellectual disability, and some with structural abnormalities (dysmorphisms, structural brain changes, mild congenital heart defects). Muscle biopsies showed COX-negative fibers and reduced activities of mitochondrial respiratory chain complexes I/III/IV. Brain imaging revealed microcephaly, septo-optic dysplasia, cerebral atrophy, and agenesis of the corpus callosum. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function (mt-tRNA processing for mitochondrial translation) shared with other genes associated with primary mitochondrial disease, functional alteration in patient cells, model organisms, and rescue in patient cells (PMIDs: 24901367, 32376682, 26857223). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 13, 2022 (SOP Version 9).

combined oxidative phosphorylation deficiency 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054742

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation deficiency 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054742

Submitter: G2P

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 35AR

Manifestation: Biochemical; 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

Refs: 28185376; 24901367

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRIT1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 110

Inborn genetic diseasesTotal: 53

Combined oxidative phosphorylation deficiency 35Total: 37

TRIT1-related disorderTotal: 12

not specifiedTotal: 7

TRIT1 DeficiencyTotal: 6

Epileptic encephalopathyTotal: 1

Possible mitochondrial disorder - nuclear genesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017646.6. 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			2 clinvar	20 clinvar		22
missense		7 clinvar	90 clinvar	9 clinvar		106
nonsense	3 clinvar	4 clinvar	1 clinvar			8
start loss						0
frameshift	2 clinvar	5 clinvar				7
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	5	17	94	29	0	145

Highest pathogenic variant AF is 0.00071801955

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017646.6	RefSeq	NP_060116.2	11	MANE Select
ENST00000316891.10	Ensembl	ENSP00000321810.5	11	MANE Select
NM_001312691.1	RefSeq	NP_001299620.1	10	Standard
NM_001312692.1	RefSeq	NP_001299621.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

tRNA modification in the nucleus and cytosol
tRNA processing
tRNA modification in the mitochondrion
Metabolism of RNA

Biological Process

tRNA modification
mitochondrial tRNA modification

Molecular Function

nucleic acid binding
ATP binding
zinc ion binding
tRNA dimethylallyltransferase activity

Cellular Component

cellular_component
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000316891
Coding exons: 11
Length: 42461
Individuals with no LoFs: 125413
Homozygous LoFs: 0
Heterozygous LoFs: 335
Defined: 125748
p: 0.00133

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.783	227	263	0.864	0.0000136	3062
Missense (PolyPhen)		65	87.865	0.73977		1026
Synonymous	0.977	81	93.0	0.871	0.00000456	894
Loss of Function	1.01	19	24.4	0.780	0.00000136	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00051	0.00049	rare
Latino/Admixed American	0.00090	0.00090	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.0025	0.0025	notable
European (Non-Finnish)	0.0018	0.0018	notable
South Asian	0.0012	0.0012	notable
Other	0.0010	0.00098	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i(6)A). {ECO:0000269|PubMed:11111046, ECO:0000269|PubMed:24901367}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 35 (COXPD35) [MIM:617873]: An autosomal recessive disorder caused by defective mitochondrial metabolism and deficiencies of mitochondrial respiratory enzyme complexes. Clinical manifestations include global developmental delay, intellectual disability, microcephaly, and early-onset seizures. {ECO:0000269|PubMed:24901367, ECO:0000269|PubMed:28185376}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.144

Intolerance Scores

LoFtool: 0.904
RVIS EVS: 0
RVIS percentile EVS: 53.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.578

Gene Damage Prediction

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