THG1L

protein-coding

tRNA-histidine guanylyltransferase 1 like

Gene summary

The protein encoded by this gene is a mitochondrial protein that is induced by high levels of glucose and is associated with diabetic nephropathy. The encoded protein appears to increase mitochondrial biogenesis, which could lead to renal fibrosis. Another function of this protein is that of a guanyltransferase, adding GMP to the 5' end of tRNA(His). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

MANE transcript

NM_017872.5

Inheritance

AR, AD

ClinVar variants

P:5U:59B:6

Top phenotype

Spinocerebellar ataxia, autosomal recessive 28

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr5:157,731,420-157,741,449

External References & Databases

Ensembl (ENSG00000113272)

Transcript & Mutation Effects

hg38 • Region Span ~10.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia, autosomal recessive 28STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032923

Submitter: PanelApp Australia

spinocerebellar ataxia, autosomal recessive 28STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032923

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia, autosomal recessive 28LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032923

Submitter: ClinGen

tRNA-histidine guanylyltransferase 1-like protein (THG1L) was first reported in relation to autosomal recessive spinocerebellar ataxia in 2016 (Edvardson et al., PMID: 27307223). Cases with *THG1L* variants have been reported with a variety of phenotypes that can include but are not limited to: cerebellar ataxia, cerebellar atrophy or hypoplasia, global developmental delay, and seizures. Dysmorphic features like microcephaly and micrognathia have been reported but in a minority of cases. Five variants (4 missense and 1 splice-region) that have been reported in eight probands in five publications (PMIDs: 27307223, 30214071, 31168944, 33682303, 37670026) are included in this curation. Two families were observed with variation in *THG1L* where an ataxia-like disease segregated with the variants (PMIDs: 27307223, 33682303). The mechanism of pathogenicity is unclear but thought to be loss of function leading to abnormalities in mitochondrial localization and morphology (PMID: 27307223). No conclusive experimental evidence was found to support this gene-disease relationship in a literature review. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date September 10, 2025 (SOP Version 11).

spinocerebellar ataxia, autosomal recessive 28LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032923

Submitter: G2P

spinocerebellar ataxia, autosomal recessive 28MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032923

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 28AR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic

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: 27307223; 30214071; 31168944

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THG1L variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 43

not providedTotal: 19

Spinocerebellar ataxia, autosomal recessive 28Total: 8

not specifiedTotal: 5

Neurodevelopmental disorderTotal: 2

THG1L-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017872.5. 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				4 clinvar		4
missense		3 clinvar	53 clinvar	2 clinvar		58
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		1 clinvar	4 clinvar			5
Total	1	4	59	6	0	70

Highest pathogenic variant AF is 0.000099959514

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017872.5	RefSeq	NP_060342.2	6	MANE Select
ENST00000231198.12	Ensembl	ENSP00000231198.7	6	MANE Select
NM_001317824.2	RefSeq	NP_001304753.1	5	Standard
NM_001317825.2	RefSeq	NP_001304754.1	4	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
Metabolism of RNA

Biological Process

tRNA modification
tRNA processing
protein homotetramerization
tRNA 5'-end processing

Molecular Function

tRNA binding
magnesium ion binding
protein binding
ATP binding
GTP binding

Cellular Component

mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000231198
Coding exons: 6
Length: 10252
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125748
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0266	169	170	0.994	0.00000881	1988
Missense (PolyPhen)		59	65.002	0.90766		715
Synonymous	-0.590	69	63.0	1.09	0.00000349	535
Loss of Function	1.48	9	15.2	0.591	7.29e-7	173

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00017	rare
South Asian	0.00014	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adds a GMP to the 5'-end of tRNA(His) after transcription and RNase P cleavage. This step is essential for proper recognition of the tRNA and for the fidelity of protein synthesis. {ECO:0000269|PubMed:21059936}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.727
RVIS EVS: -0.25
RVIS percentile EVS: 35.75

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.903

Gene Damage Prediction

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