TRMU

protein-coding

tRNA mitochondrial 2-thiouridylase

Gene summary

This nuclear gene encodes a mitochondrial tRNA-modifying enzyme. The encoded protein catalyzes the 2-thiolation of uridine on the wobble positions of tRNA(Lys), tRNA(Glu), and tRNA(Gln), resulting in the formation of 5-taurinomethyl-2-thiouridine moieties. Mutations in this gene may cause transient infantile liver failure. Polymorphisms in this gene may also influence the severity of deafness caused by mitochondrial 12S ribosomal RNA mutations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

Previous symbols:

TRMT

MANE transcript

NM_018006.5

Inheritance

Mitochondrial, AR, AD

ClinVar variants

P:204U:172B:245

Top phenotype

Deafness, aminoglycoside-induced; Liver failure, infantile, transient; Reversible infantile respiratory chain deficiency

gnomAD constraint

pLI —, LoF o/e 1.1

Max pathogenic AF

—

Genomic locus

chr22:46,330,875-46,357,340

External References & Databases

Ensembl (ENSG00000100416)

Transcript & Mutation Effects

hg38 • Region Span ~26.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial myopathy with reversible cytochrome C oxidase deficiencySUPPORTIVE

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010780

Submitter: Orphanet

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013111

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TRMU* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 23, 2024. The *TRMU* gene encodes the tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, a mitochondrion-specific tRNA-modifying enzyme. *TRMU* was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19732863). While various names have been given to the constellation of features seen in those with *TRMU*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TRMU phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *TRMU* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on December 16, 2020 (SOP V7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the three cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven missense variants, two nonsense variants, one frameshift variant and one variant predicted to impact splicing in eight cases from six publications (PMIDs: 23625533, 28562522, 30740308, 33205917, 33365252, 36305855). However there have been at least 60 cases reported in the medical literature (PMID: 36305855). Affected individuals have a spectrum of clinical features including fatal infantile multiorgan system failure, LSS, and acute infantile liver failure that may spontaneously resolve. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of *TRMU* in modification of mitochondrial tRNAs, as well as functional alteration in patient cells (PMID: 21153446) and several model systems including nematode (PMID: 28732077), zebrafish (PMID: 30137487), and mouse (PMID: 27689697). In summary, there is definitive evidence to support the relationship between *TRMU* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 23, 2024 (SOP Version 10).

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TRMU and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 23, 2020. The TRMU gene encodes the tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, a mitochondrion-specific tRNA-modifying enzyme. The TRMU gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 25058219). Of note, many individuals with TRMU-related disease have so-called “reversible” infantile liver failure without features of Leigh syndrome spectrum. Evidence supporting the gene-disease relationship between TRMU and Leigh syndrome spectrum includes case-level data and experimental data. This curation included five variants identified in three cases in two publications (PMID: 25058219, 33365252). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function and animal models (PMIDs: 29980628, 27689697). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 16, 2020 (SOP Version 7).

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013111

Submitter: Ambry Genetics

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013111

Submitter: PanelApp Australia

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013111

Submitter: Natera

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013111

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, aminoglycoside-induced; Liver failure, infantile, transient; Reversible infantile respiratory chain deficiencyAD/AR

Manifestation: Biochemical; Gastrointestinal

Intervention: Gastrointestinal; Pharmacogenomic

Rationale: Individuals with aminoglycoside-induced deafness may be at risk of deafness when treated with certain antibiotics; In Liver failure, infantile, transient, with supportive care, patients surviving the initial acute episode can recover and demonstrate typical development; Genetic diagnosis may be beneficial in order to determine therapy

Comments: The inheritance of aminoglycoside-induced deafness may involve multiple, co-segregating variants

Refs: 7689389; 11230176; 12408186; 16152638; 19732863; 21931168; 21931168

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRMU variants in ClinVar

9 Conditions Cataloged

not providedTotal: 633

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsTotal: 227

Aminoglycoside-induced deafnessTotal: 91

TRMU-related disorderTotal: 84

Inborn genetic diseasesTotal: 71

not specifiedTotal: 55

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Possible mitochondrial disorder - nuclear genesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018006.5. 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			8 clinvar	217 clinvar	5 clinvar	230
missense	2 clinvar	20 clinvar	158 clinvar	18 clinvar	5 clinvar	203
nonsense	15 clinvar	19 clinvar	2 clinvar			36
start loss	1 clinvar	2 clinvar				3
frameshift	50 clinvar	52 clinvar	2 clinvar			104
splice donor/acceptor (+/-2bp)	3 clinvar	40 clinvar	2 clinvar			45
Total	71	133	172	235	10	621

Highest pathogenic variant AF is 0.00020631842

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 115 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018006.5	RefSeq	NP_060476.2	11	MANE Select
ENST00000645190.1	Ensembl	ENSP00000496496.1	11	MANE Select
NM_001282782.2	RefSeq	NP_001269711.1	9	Standard
NM_001282783.2	RefSeq	NP_001269712.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

tRNA wobble position uridine thiolation

Molecular Function

tRNA binding
ATP binding
sulfurtransferase activity

Cellular Component

nucleoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290846
Coding exons: 11
Length: 26466
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.332	247	233	1.06	0.0000129	2766
Missense (PolyPhen)		90	97.855	0.91973		1185
Synonymous	-3.15	131	92.5	1.42	0.00000546	802
Loss of Function	-0.439	23	20.8	1.10	9.74e-7	241

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00065	0.00065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). Required for the formation of 5-taurinomethyl-2- thiouridine (tm5s2U) of mitochondrial tRNA(Lys), tRNA(Glu), and tRNA(Gln) at the wobble position. ATP is required to activate the C2 atom of the wobble base. {ECO:0000269|PubMed:15509579, ECO:0000269|PubMed:15944150, ECO:0000269|PubMed:16826519}.;
Disease: DISEASE: Liver failure, infantile, transient (LFIT) [MIM:613070]: A transient disorder of hepatic function characterized by elevated liver enzymes, jaundice, vomiting, coagulopathy, hyperbilirubinemia, increased serum lactate. Patients who survive the initial acute episode can recover, show normal development and have no recurrence. {ECO:0000269|PubMed:19732863}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.234

Intolerance Scores

LoFtool: 0.835
RVIS EVS: -0.07
RVIS percentile EVS: 48.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.230

Gene Damage Prediction

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