TRMT2A

Chr 22

tRNA methyltransferase 2A

ENSG00000099899 UniProt: Q8IZ69 OMIM: 611151

The encoded protein is an S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the formation of 5-methyl-uridine in tRNAs and some mRNAs, primarily methylating uridine at position 54 in cytosolic tRNAs. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the formation of 5-methyl-uridine in tRNAs and some mRNAs (PubMed:31361898, PubMed:33799331, PubMed:34556860). Mainly catalyzes the methylation of uridine at position 54 (m5U54) in cytosolic tRNAs (PubMed:31361898, PubMed:33799331). Also able to mediate the formation of 5-methyl-uridine in some mRNAs (PubMed:34123281)

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.92

Clinical Summary— TRMT2A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.88

OE 0.61 (0.42–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.13Z-score

OE missense 1.02 (0.94–1.11)

405 obs / 397.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.61 (0.42–0.92)

0≤0.351.4

Missense OE?1.02 (0.94–1.11)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 17 / 27.7Missense obs/exp: 405 / 397.6Syn Z: -2.01

This gene — mechanism propensity

0.6745th %ile

GOF

0.5268th %ile

LOF

0.3065th %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.