TRMT5

Chr 14AR

tRNA methyltransferase 5

Also known as: COXPD26, KIAA1393, PNSED, TRM5

NCBI Gene: 57570 ENSG00000126814 UniProt: Q32P41 OMIM: 611023

TRMT5 encodes a methyltransferase that specifically methylates guanosine-37 in various tRNAs, which is the first step in biosynthesis of wybutosine, a modified base required for accurate decoding during protein translation. Biallelic mutations cause autosomal recessive peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.588), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

tRNAs contain as many as 13 or 14 nucleotides that are modified posttranscriptionally by enzymes that are highly specific for particular nucleotides in the tRNA structure. TRMT5 methylates the N1 position of guanosine-37 (G37) in selected tRNAs using S-adenosyl methionine (Brule et al., 2004 [PubMed 15248782]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.591 OMIM phenotype

Clinical Summary— TRMT5

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 148 VUS of 275 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.050

Z-score 2.92

OE 0.30 (0.16–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.10Z-score

OE missense 0.98 (0.89–1.09)

252 obs / 256.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.16–0.59)

0≤0.351.4

Missense OE?0.98 (0.89–1.09)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 6 / 20.1Missense obs/exp: 252 / 256.6Syn Z: -0.80

This gene — mechanism propensity

0.6937th %ile

GOF

0.3788th %ile

LOF

0.3162th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

275 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS148

Likely Benign89

Benign14

Conflicting8

Pathogenic

Likely Pathogenic

148

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	2	0	0	0	2
VUS	13	123	10	2	148
Likely Benign	0	8	20	61	89
Benign	0	4	7	3	14
Conflicting	—				8
Total	15	136	37	66	262

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap TRMT5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →