TRMT1

protein-coding

tRNA methyltransferase 1, the group of 7BS DNA/RNA methyltransferases

Gene summary

This gene encodes a tRNA-modifying enzyme that acts as a dimethyltransferase, modifying a single guanine residue at position 26 of the tRNA. The encoded enzyme has both mono- and dimethylase activity when exogenously expressed, and uses S-adenosyl methionine as a methyl donor. The C-terminal region of the encoded protein has both a zinc finger motif, and an arginine/proline-rich region. Mutations in this gene have been implicated in autosomal recessive intellectual disorder (ARID). Alternative splicing results in multiple transcript variants encoding different isoforms. There is a pseudogene of this gene on the X chromosome. [provided by RefSeq, May 2017]

MANE transcript

NM_001136035.4

Inheritance

AR, AD

ClinVar variants

P:35U:165B:40

Top phenotype

Intellectual developmental disorder, autosomal recessive 68

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr19:13,104,902-13,117,567

External References & Databases

Ensembl (ENSG00000104907)

Transcript & Mutation Effects

hg38 • Region Span ~12.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 68STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032665

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 68LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032665

Submitter: G2P

intellectual developmental disorder, autosomal recessive 68STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032665

Submitter: Labcorp Genetics (formerly Invitae)

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 68DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032665

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

The *TRMT1* gene encodes a tRNA methyltransferase involved in post-transcriptional RNA modification. *TRMT1* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2011 (Najmabadi et al., PMID: 21937992). Clinical features include global developmental delay, intellectual disability, language deficits, and mild facial dysmorphism. Additional features in a subset of individuals can include behavioral abnormalities, seizures, microcephaly, short stature, gait abnormalities or poor coordination, and cerebral and/or cerebellar atrophy. Eleven variants (4 frameshift, 4 splice site, 2 nonsense and 1 missense) that have been reported in 10 probands in 5 publications (PMIDs: 21937992, 26308914, 30289604, 31898845, 40245862) are included in this curation. Variants in *TRMT1* segregated with disease in 7 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence, including biochemical function, a zebrafish model and *in vitro* functional studies. Defects in multiple tRNA methyltransferases (*TRMT10A*, *WDR4*, *FTSJ1*, *ALKBH8*, *NSUN2*, and *NSUN6*) have been implicated in neurodevelopmental disorders with overlapping clinical features (PMID: 30415557). *TRMT1* knockout zebrafish have reduced brain and body size, increased locomotor behavior and decreased neuronal cell proliferation (PMID: 40245862). Patient-derived fibroblasts and lymphoblastoid cell lines harbouring bi-allelic *TRMT1* variants demonstrate significantly reduced levels of N2,N2-dimethylguanosine (m2,2G) in tRNA (PMID: 40245862). In summary, there is definitive evidence supporting the relationship between *TRMT1* and autosomal recessive complex neurodevelopmental disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on March 4, 2026 (SOP version 12).

intellectual developmental disorder, autosomal recessive 68MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032665

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 68AR

Manifestation: Craniofacial; Musculoskeletal; 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: 21937992; 26308914; 30289604

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRMT1 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 146

not providedTotal: 77

Intellectual developmental disorder, autosomal recessive 68Total: 36

not specifiedTotal: 9

TRMT1-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001136035.4. 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			3 clinvar	29 clinvar	1 clinvar	33
missense		2 clinvar	155 clinvar	10 clinvar		167
nonsense	4 clinvar	7 clinvar	2 clinvar			13
start loss			1 clinvar			1
frameshift	7 clinvar	9 clinvar				16
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	4 clinvar			10
Total	12	23	165	39	1	240

Highest pathogenic variant AF is 0.00021877362

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 102 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001136035.4	RefSeq	NP_001129507.1	16	MANE Select
ENST00000357720.9	Ensembl	ENSP00000350352.4	16	MANE Select
NM_001142554.3	RefSeq	NP_001136026.1	15	Standard
NM_001351760.2	RefSeq	NP_001338689.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
tRNA modification in the nucleus and cytosol
tRNA processing
Metabolism of RNA

Biological Process

tRNA N2-guanine methylation
tRNA modification

Molecular Function

tRNA binding
RNA binding
tRNA (guanine-N2-)-methyltransferase activity
protein binding
metal ion binding

Cellular Component

nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000592062
Coding exons: 16
Length: 12666
Individuals with no LoFs: 125655
Homozygous LoFs: 0
Heterozygous LoFs: 92
Defined: 125747
p: 0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.561	406	439	0.925	0.0000290	4224
Missense (PolyPhen)		71	94.709	0.74966		913
Synonymous	-0.320	185	180	1.03	0.0000121	1372
Loss of Function	1.82	24	35.7	0.672	0.00000204	359

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00071	0.00071	rare
Finnish	0.000096	0.000092	rare
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00062	0.00062	rare
Other	0.00085	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl-L-methionine as donor of the methyl groups.;

Recessive Scores

pRec: 0.123

Intolerance Scores

LoFtool: 0.0725
RVIS EVS: -0.8
RVIS percentile EVS: 12.53

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.951

Gene Damage Prediction

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