TRNT1

Summary

TRNT1 (tRNA nucleotidyl transferase 1, HGNC:17341) is a protein-coding gene on chromosome 3p26.2, encoding CCA tRNA nucleotidyltransferase 1, mitochondrial (Q96Q11). Nucleotidyltransferase that catalyzes the addition and repair of the essential 3’-terminal CCA sequence in tRNAs, which is necessary for the attachment of amino acids to the 3’ terminus of tRNA molecules, using CTP and ATP as substrates. tRNA 3’-terminal CCA addition is required…. It is a common-essential gene (DepMap: required in 99.3% of cancer cell lines).

The protein encoded by this gene is a CCA-adding enzyme which belongs to the tRNA nucleotidyltransferase/poly(A) polymerase family. This essential enzyme functions by catalyzing the addition of the conserved nucleotide triplet CCA to the 3’ terminus of tRNA molecules. Mutations in this gene result in sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51095 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 646 total — 66 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 53
• Cancer dependency (DepMap): dependent in 99.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_182916

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17341
Approved symbol	TRNT1
Name	tRNA nucleotidyl transferase 1
Location	3p26.2
Locus type	gene with protein product
Status	Approved
Aliases	MtCCA, CGI-47, CCA1
Ensembl gene	ENSG00000072756
Ensembl biotype	protein_coding
OMIM	612907
Entrez	51095

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 24 protein_coding, 11 nonsense_mediated_decay, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000251607, ENST00000280591, ENST00000339437, ENST00000397779, ENST00000402675, ENST00000413000, ENST00000420393, ENST00000434583, ENST00000465998, ENST00000469632, ENST00000482311, ENST00000650755, ENST00000650814, ENST00000650839, ENST00000650989, ENST00000651093, ENST00000651316, ENST00000651352, ENST00000651591, ENST00000652340, ENST00000698406, ENST00000698407, ENST00000698408, ENST00000698409, ENST00000698410, ENST00000698411, ENST00000698412, ENST00000698413, ENST00000698414, ENST00000698415, ENST00000698416, ENST00000866261, ENST00000866262, ENST00000866263, ENST00000866264, ENST00000925748, ENST00000925749, ENST00000925750, ENST00000925751, ENST00000970527, ENST00000970528, ENST00000970529

RefSeq mRNA: 5 — MANE Select: NM_182916 NM_001302946, NM_001367321, NM_001367322, NM_001367323, NM_182916

CCDS: CCDS2561, CCDS77691

Canonical transcript exons

ENST00000251607 — 8 exons

Exon	Start	End
ENSE00001528667	3147906	3149023
ENSE00003664355	3129014	3129188
ENSE00003843679	3126940	3126990
ENSE00003973563	3140510	3140648
ENSE00003973573	3144584	3144710
ENSE00003973575	3137260	3137453
ENSE00003973577	3147450	3147703
ENSE00003973585	3146430	3146623

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 94.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.8724 / max 221.5980, expressed in 1806 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35019	17.4841	1806
35020	0.6396	330
35021	0.6383	293
35022	0.1104	37

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	94.96	gold quality
secondary oocyte	CL:0000655	93.04	gold quality
oocyte	CL:0000023	91.83	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.38	gold quality
calcaneal tendon	UBERON:0003701	90.37	gold quality
adrenal tissue	UBERON:0018303	89.82	gold quality
parietal pleura	UBERON:0002400	89.37	gold quality
colonic epithelium	UBERON:0000397	89.16	gold quality
epithelial cell of pancreas	CL:0000083	88.21	gold quality
cartilage tissue	UBERON:0002418	87.80	gold quality
metanephros	UBERON:0000081	87.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.58	gold quality
tibia	UBERON:0000979	87.45	gold quality
cortical plate	UBERON:0005343	87.41	gold quality
vermiform appendix	UBERON:0001154	87.40	gold quality
sural nerve	UBERON:0015488	87.39	gold quality
bone marrow cell	CL:0002092	87.33	gold quality
visceral pleura	UBERON:0002401	87.24	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.89	gold quality
islet of Langerhans	UBERON:0000006	86.88	gold quality
monocyte	CL:0000576	86.84	gold quality
rectum	UBERON:0001052	86.80	gold quality
germinal epithelium of ovary	UBERON:0001304	86.74	gold quality
smooth muscle tissue	UBERON:0001135	86.73	gold quality
leukocyte	CL:0000738	86.63	gold quality
endometrium	UBERON:0001295	86.45	gold quality
prostate gland	UBERON:0002367	86.36	gold quality
lymph node	UBERON:0000029	86.34	gold quality
metanephros cortex	UBERON:0010533	86.10	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.93	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CLOCK

miRNA regulators (miRDB)

52 targeting TRNT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-323B-3P	99.14	68.89	725
HSA-MIR-5100	99.11	67.52	1098

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 22)

• human gene transcript CGI-47 (#AF151805) was cloned and encodes a bona fide CCA-adding enzyme and not a poly(A) polymerase. (PMID:11727826)
• The crystal structure reveals a four domain architecture with a cluster of conserved residues forming a positively charged cleft between the first two domains. (PMID:12729736)
• These findings strongly suggest that the splice variant of the human CCA-adding enzyme is expressed in the cell although the in vivo function remains unclear. (PMID:17204286)
• is a RNA polymerase which newly adds CCA sequence to tRNA 3’terminal. This reaction was named as Vice-Anchored Knock-in and Lock Dynamics.[review] (PMID:18575231)
• The patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy. (PMID:25193871)
• Tandem CCA addition is not the result of a modified enzymatic activity that is particular to unstable RNAs. Rather, it is a consequence of the natural activity of the CCA-adding enzyme on a substrate with increased conformational flexibility, the CCA-adding enzyme is able to trigger the degradation of potentially detrimental small RNAs and tRNAs. (PMID:25640237)
• The clinical phenotypes associated with TRNT1 mutations are largely due to impaired mitochondrial translation, resulting from defective CCA addition to mitochondrial tRNA(Ser(AGY)). (PMID:25652405)
• A model of action is proposed, where motif C forms a flexible spring element modulating the relative orientation of the enzyme’s head and body domains to accommodate the growing 3’-end of the tRNA. (PMID:25849199)
• The discriminator base represents an important substrate recognition element for tRNA nucleotidyltransferases. (PMID:25958396)
• two non-syndromic retinitis pigmentosa pedigrees with segregating mutations in TRNT1 (PMID:26494905)
• Data show that the disease causing mutations in patient-derived fibroblasts do not affect subcellular localization of TRNT1 and show no gross morphological differences when compared to control cells. (PMID:27317422)
• family expands the ocular and systemic phenotypes associated with mutations in TRNT1, demonstrating phenotypic variability and highlighting the need for ophthalmic review of these patients. (PMID:27389523)
• patient-specific induced pluripotent stem cells (iPSCs) and iPSC-derived retinal organoids from dermal fibroblasts of patients with molecularly confirmed TRNT1-associated retinitis pigmentosa. (PMID:28390992)
• We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay. Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. (PMID:29358286)
• In vitro studies of disease-linked variants of human tRNA nucleotidyltransferase reveal decreased thermal stability and altered catalytic activity. (PMID:29454993)
• Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow. (PMID:30758723)
• In vitro analysis revealed that the I326T substitution decreases the thermal stability of TRNT1 and causes a ten-fold reduction in enzyme activity. These data suggest that the structural changes in the I326T variant result from a rearrangement of helices within the body domain of the protein which can be probed by the inability of the monomeric enzyme to form a covalent dimer in vitro. (PMID:30959222)
• The expression of mitochondrial non-coding RNAs regulated by TRNT1 has been described. (PMID:31512554)
• Two cases of sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) syndrome in Chinese Han children caused by novel compound heterozygous variants of the TRNT1 gene. (PMID:34310935)
• A phenotypic expansion of TRNT1 associated sideroblastic anemia with immunodeficiency, fevers, and developmental delay. (PMID:34510712)
• Genes for tRNA recycling are upregulated in response to infection with Theiler’s mouse encephalitis virus. (PMID:34864548)
• TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins. (PMID:37239403)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	trnt1	ENSDARG00000075297
mus_musculus	Trnt1	ENSMUSG00000013736
rattus_norvegicus	Trnt1	ENSRNOG00000006432
rattus_norvegicus	LOC100911093	ENSRNOG00000020477
drosophila_melanogaster	CG2100	FBGN0037369
caenorhabditis_elegans		WBGENE00010089

Protein

Protein identifiers

CCA tRNA nucleotidyltransferase 1, mitochondrial — Q96Q11 (reviewed: Q96Q11)

Alternative names: Mitochondrial tRNA nucleotidyl transferase, CCA-adding, mt CCA-adding enzyme, mt tRNA CCA-diphosphorylase, mt tRNA CCA-pyrophosphorylase, mt tRNA adenylyltransferase

All UniProt accessions (13): Q96Q11, A0A494BZV5, A0A494C0A0, A0A494C0N8, A0A494C0Y2, A0A494C181, A0A494C1D4, A0A494C1L4, A0A494C1P4, A0A8V8TM71, A0A8V8TN57, C9JRS7, F8W8C3

UniProt curated annotations — full annotation on UniProt →

Function. Nucleotidyltransferase that catalyzes the addition and repair of the essential 3’-terminal CCA sequence in tRNAs, which is necessary for the attachment of amino acids to the 3’ terminus of tRNA molecules, using CTP and ATP as substrates. tRNA 3’-terminal CCA addition is required both for tRNA processing and repair. Promotes tRNA repair and recycling downstream of the ribosome-associated quality control (RQC) pathway by mediating addition of the tRNA 3’-terminal CCA following cleavage by ANKZF1 and repair by ELAC1. Also involved in tRNA surveillance by mediating tandem CCA addition to generate a CCACCA at the 3’ terminus of unstable tRNAs and tRNA-like transcripts. While stable tRNAs receive only 3’-terminal CCA, unstable tRNAs beginning with GG are marked with CCACCA and rapidly degraded. The structural flexibility of RNA controls the choice between CCA versus CCACCA addition: following the first CCA addition cycle, nucleotide-binding to the active site triggers a clockwise screw motion, producing torque on the RNA. This ejects stable RNAs, whereas unstable RNAs are refolded while bound to the enzyme and subjected to a second CCA catalytic cycle. Adds 2 C residues (CC-) to the 3’ terminus of tRNA molecules instead of a complete CCA end as isoform 1 does (in vitro).

Subunit / interactions. Monomer, and homodimer; disulfide-linked.

Subcellular location. Mitochondrion. Cytoplasm. Nucleus.

Disease relevance. Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) [MIM:616084] An autosomal recessive disease characterized by severe sideroblastic anemia with onset in the neonatal period or infancy, recurrent periodic fevers without an infectious etiology, B-cell lymphopenia and hypogammaglobulinemia. Affected individuals show delayed psychomotor development with variable neurodegeneration. Additional variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa and erythrocytic microcytosis (RPEM) [MIM:616959] An autosomal recessive disease characterized by retinitis pigmentosa, red blood cell microcytosis and anisocytosis with mild anemia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tRNA nucleotidyltransferase/poly(A) polymerase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96Q11-1	1	yes
Q96Q11-2	2
Q96Q11-3	3

RefSeq proteins (5): NP_001289875, NP_001354250, NP_001354251, NP_001354252, NP_886552* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002646	PolA_pol_head_dom	Domain
IPR032828	PolyA_RNA-bd	Domain
IPR043519	NT_sf	Homologous_superfamily
IPR050264	Bact_CCA-adding_enz_type3_sf	Family

Pfam: PF01743, PF12627

Enzyme classification (BRENDA):

• EC 2.7.7.72 — CCA tRNA nucleotidyltransferase (BRENDA: 26 organisms, 69 substrates, 8 inhibitors, 69 Km, 50 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CTP	0.01–0.65	26
ATP	0.004–12.5	19
A TRNA PRECURSOR	0.008–0.119	4
ARMLESS TRNA(ARG) PRECURSOR	0.0013–0.0048	4
ARMLESS TRNA(ILE) PRECURSOR	0.002–0.0078	4
TRNA(PHE) PRECURSOR	0.003–0.0047	4
DIPHOSPHATE	0.5–1	3
TRNAHIS+G-1	0.0029	1
TRNAHISDELTAG-1	0.0016	1

Catalyzed reactions (Rhea), 2 shown:

• a tRNA precursor + 2 CTP + ATP = a tRNA with a 3’ CCA end + 3 diphosphate (RHEA:14433)
• a tRNA with a 3’ CCA end + 2 CTP + ATP = a tRNA with a 3’ CCACCA end + 3 diphosphate (RHEA:76235)

UniProt features (90 total): helix 25, sequence variant 24, binding site 16, strand 12, splice variant 3, site 2, modified residue 2, mutagenesis site 2, transit peptide 1, chain 1, disulfide bond 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4X4W	X-RAY DIFFRACTION	1.9
8CBM	ELECTRON MICROSCOPY	3.14
1OU5	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96Q11-F1	90.00	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 152 (may assist in discriminating atp from ctp); 193 (involved in nucleotide selection)

Ligand- & substrate-binding residues (16): 194; 194; 197; 197; 200; 200; 203; 203; 64; 64; 67; 67 …

Post-translational modifications (2): 400, 402

Disulfide bonds (1): 373

Mutagenesis-validated functional residues (2):

Position	Phenotype
326	decreased cca trna nucleotidyltransferase activity; abolished homodimerization and disulfide bond formation.
373	abolished homodimerization and disulfide bond formation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-6785470	tRNA processing in the mitochondrion

MSigDB gene sets: 227 (showing top): GOBP_TRNA_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TRANSLATION, GOBP_RNA_SURVEILLANCE, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GOBP_TRANSLATIONAL_ELONGATION, SCHLINGEMANN_SKIN_CARCINOGENESIS_TPA_UP, TURASHVILI_BREAST_CARCINOMA_DUCTAL_VS_LOBULAR_UP, GOBP_TRNA_PROCESSING, GOBP_ORGANELLE_DISASSEMBLY, REACTOME_METABOLISM_OF_RNA, GOCC_MITOCHONDRIAL_MATRIX, chr3p26, GOMF_PROTEIN_DIMERIZATION_ACTIVITY

GO Biological Process (7): tRNA 3’-terminal CCA addition (GO:0001680), tRNA 3’-end processing (GO:0042780), rescue of stalled cytosolic ribosome (GO:0072344), tRNA surveillance (GO:0106354), mitochondrial tRNA 3’-end processing (GO:1990180), RNA processing (GO:0006396), tRNA processing (GO:0008033)

GO Molecular Function (12): tRNA binding (GO:0000049), CCA tRNA nucleotidyltransferase activity (GO:0004810), ATP binding (GO:0005524), 5’-3’ RNA polymerase activity (GO:0034062), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), CCACCA tRNA nucleotidyltransferase activity (GO:0160016), nucleotide binding (GO:0000166), RNA binding (GO:0003723), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
tRNA 3’-end processing	2
mitochondrion	2
cytidylyltransferase activity	2
catalytic activity, acting on a tRNA	2
intracellular membrane-bounded organelle	2
cytoplasm	2
CCA tRNA nucleotidyltransferase activity	1
CC tRNA cytidylyltransferase activity	1
ATP:3’-cytidine-cytidine-tRNA adenylyltransferase activity	1
tRNA processing	1
RNA 3’-end processing	1
cytoplasmic translational elongation	1
ribosome disassembly	1
tRNA decay	1
RNA surveillance	1
mitochondrial RNA 3’-end processing	1
mitochondrial tRNA processing	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA processing	1
tRNA metabolic process	1
RNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
RNA polymerase activity	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nuclear lumen	1
intracellular organelle lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2907 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRNT1	CRYGD	P07320	832
TRNT1	CRYBB2	P43320	803
TRNT1	PRR9	Q5T870	795
TRNT1	GCNT2	Q8N0V5	779
TRNT1	CRYGB	P07316	762
TRNT1	CRYBB3	P26998	756
TRNT1	MAF	O75444	735
TRNT1	ELAC2	Q9BQ52	716
TRNT1	CRYGA	P11844	650
TRNT1	ELAC1	Q9H777	640
TRNT1	CRYGC	P07315	639
TRNT1	TRIT1	Q9H3H1	621
TRNT1	PUS1	Q9Y606	604
TRNT1	THG1L	Q9NWX6	591
TRNT1	PRR7	Q8TB68	582

IntAct

17 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TRNT1	NARS2	psi-mi:“MI:0915”(physical association)	0.400
nleF	TRNT1	psi-mi:“MI:0915”(physical association)	0.370
TRNT1	nleF	psi-mi:“MI:0915”(physical association)	0.370
P		psi-mi:“MI:0914”(association)	0.350
EPSTI1	CST4	psi-mi:“MI:0914”(association)	0.350
SELENBP1	ZNF24	psi-mi:“MI:0914”(association)	0.350
NTNG1	UBA6	psi-mi:“MI:0914”(association)	0.350
TRNT1	H1-3	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
KRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
	TRNT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (58): DPYD (Co-fractionation), SH3BP1 (Co-fractionation), TRNT1 (Co-fractionation), TRNT1 (Co-fractionation), TRNT1 (Co-fractionation), TRNT1 (Co-fractionation), NARS2 (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), TRNT1 (Affinity Capture-RNA), TRNT1 (Affinity Capture-MS), TRNT1 (Affinity Capture-MS), TRNT1 (Negative Genetic), TRNT1 (Affinity Capture-MS), TRNT1 (Affinity Capture-MS), TRNT1 (Affinity Capture-MS)

ESM2 similar proteins: A0Q8A2, A1AVT4, A1SRC9, A5UCK0, A5UJ23, A6VN94, A8F1N7, A8GS87, A9KEZ9, A9NAS1, B0BXQ1, B0UUU5, B4RVV4, B5RLZ3, B5RRN9, C4K6G4, P45269, P47520, P47700, Q05770, Q06461, Q07YU1, Q12KC4, Q14JW7, Q1LSL7, Q1RH40, Q1RIZ9, Q30SG7, Q493X4, Q4UNJ0, Q5NIG4, Q5QY23, Q65Q41, Q68VR6, Q68WH7, Q68WX4, Q7U350, Q820V9, Q8K1J6, Q8KA53

Diamond homologs: A0AK10, A2RF34, A2RJT1, A3CMU4, A4IQ63, A4VUK6, A4W0U8, A5VJK7, A6QH08, A7GN74, A7X2F4, A7Z5Z6, A8AX96, A8FEH9, A8YV39, A8Z437, A9VME7, B1MYC1, B2G721, B2GC39, B2IR74, B3WE84, B5E6J9, B7GHS8, B7HHU0, B7HL50, B7IPB4, B7JH21, B8DC21, B9DNX1, B9DRX9, B9IVQ9, C1EN33, C1KWK5, C3L8Q3, C3P5Q6, C5D3B5, F6NXI9, P0DA18, P0DA19

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

646 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	66
Likely pathogenic	9
Uncertain significance	295
Likely benign	193
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068618	NM_182916.3(TRNT1):c.33_46del (p.Leu13fs)	Pathogenic
1068812	NM_182916.3(TRNT1):c.73C>T (p.Gln25Ter)	Pathogenic
1070063	NM_182916.3(TRNT1):c.851dup (p.Asn284fs)	Pathogenic
1070580	NM_182916.3(TRNT1):c.442dup (p.Ala148fs)	Pathogenic
1074520	NM_182916.3(TRNT1):c.711del (p.Ile238fs)	Pathogenic
1074723	NM_182916.3(TRNT1):c.240del (p.Phe80fs)	Pathogenic
1075271	NM_182916.3(TRNT1):c.1178_1184del (p.Ile393fs)	Pathogenic
1370253	NM_182916.3(TRNT1):c.1055_1056+5del	Pathogenic
1371643	NM_182916.3(TRNT1):c.847A>T (p.Lys283Ter)	Pathogenic
1388100	NM_182916.3(TRNT1):c.608+1G>A	Pathogenic
1400916	NM_182916.3(TRNT1):c.996_999del (p.Asp332fs)	Pathogenic
1406480	NM_182916.3(TRNT1):c.778del (p.Asp260fs)	Pathogenic
1408061	NM_182916.3(TRNT1):c.809del (p.Pro270fs)	Pathogenic
1417619	NM_182916.3(TRNT1):c.1190del (p.Gly397fs)	Pathogenic
1428404	NM_182916.3(TRNT1):c.974_977del (p.Leu324_Phe325insTer)	Pathogenic
1443740	NM_182916.3(TRNT1):c.428_431del (p.Asp143fs)	Pathogenic
1447899	NM_182916.3(TRNT1):c.263_266del (p.Gln88fs)	Pathogenic
1452239	NM_182916.3(TRNT1):c.1252_1253insT (p.Ser418fs)	Pathogenic
1454659	NC_000003.11:g.(?3170725)(3189838_?)del	Pathogenic
1457594	NM_182916.3(TRNT1):c.622_623del (p.Ile208fs)	Pathogenic
1458074	NM_182916.3(TRNT1):c.1053_1054insT (p.Asp352Ter)	Pathogenic
157613	NM_182916.3(TRNT1):c.569G>T (p.Arg190Ile)	Pathogenic
157614	NM_182916.3(TRNT1):c.668T>C (p.Ile223Thr)	Pathogenic
157616	NM_182916.3(TRNT1):c.497T>C (p.Leu166Ser)	Pathogenic
157617	NM_182916.3(TRNT1):c.461C>T (p.Thr154Ile)	Pathogenic
157618	NM_182916.3(TRNT1):c.1142_1143insATGT (p.Trp381Ter)	Pathogenic
1896137	NM_182916.3(TRNT1):c.433C>T (p.Gln145Ter)	Pathogenic
1904390	NM_182916.3(TRNT1):c.569_570del (p.Arg190fs)	Pathogenic
1939998	NM_182916.3(TRNT1):c.1012_1013del (p.Thr337_Asp338insTer)	Pathogenic
2009367	NM_182916.3(TRNT1):c.176_182del (p.Glu58_Leu59insTer)	Pathogenic

SpliceAI

1886 predictions. Top by Δscore:

Variant	Effect	Δscore
3:3130023:C:G	donor_gain	1.0000
3:3137258:A:AG	acceptor_gain	1.0000
3:3137259:G:GG	acceptor_gain	1.0000
3:3137259:GA:G	acceptor_gain	1.0000
3:3137259:GAATT:G	acceptor_gain	1.0000
3:3137452:GG:G	donor_gain	1.0000
3:3137453:GG:G	donor_gain	1.0000
3:3146532:GATT:G	donor_gain	1.0000
3:3151043:TAC:T	acceptor_gain	1.0000
3:3151046:CTAAG:C	acceptor_loss	1.0000
3:3153418:CCTTA:C	donor_loss	1.0000
3:3153419:CTTA:C	donor_loss	1.0000
3:3153420:TTA:T	donor_loss	1.0000
3:3126946:G:GT	donor_gain	0.9900
3:3126986:GGCCG:G	donor_gain	0.9900
3:3126987:GCCGG:G	donor_gain	0.9900
3:3126988:CCGGT:C	donor_loss	0.9900
3:3126989:CG:C	donor_loss	0.9900
3:3126990:GG:G	donor_loss	0.9900
3:3126991:G:GG	donor_gain	0.9900
3:3126992:T:TC	donor_loss	0.9900
3:3127520:G:GT	donor_gain	0.9900
3:3127538:G:T	donor_gain	0.9900
3:3127584:G:GT	donor_gain	0.9900
3:3127585:A:T	donor_gain	0.9900
3:3127596:G:GT	donor_gain	0.9900
3:3127597:A:T	donor_gain	0.9900
3:3129012:A:AG	acceptor_gain	0.9900
3:3129013:G:GG	acceptor_gain	0.9900
3:3129013:GAT:G	acceptor_gain	0.9900

AlphaMissense

2874 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:3140619:G:C	R151T	0.999
3:3140622:A:C	D152A	0.999
3:3144682:G:C	D194H	0.999
3:3144710:G:T	R203M	0.999
3:3140597:T:A	W144R	0.998
3:3140597:T:C	W144R	0.998
3:3140606:G:C	D147H	0.998
3:3140619:G:T	R151I	0.998
3:3140620:A:C	R151S	0.998
3:3140620:A:T	R151S	0.998
3:3140622:A:T	D152V	0.998
3:3140623:T:A	D152E	0.998
3:3140623:T:G	D152E	0.998
3:3140625:T:C	L153P	0.998
3:3144683:A:C	D194A	0.998
3:3144683:A:T	D194V	0.998
3:3144684:T:A	D194E	0.998
3:3144684:T:G	D194E	0.998
3:3144692:G:C	R197T	0.998
3:3137348:T:A	D79E	0.997
3:3137348:T:G	D79E	0.997
3:3140609:G:C	A148P	0.997
3:3140615:C:A	R150S	0.997
3:3140621:G:C	D152H	0.997
3:3140622:A:G	D152G	0.997
3:3140635:T:A	N156K	0.997
3:3140635:T:G	N156K	0.997
3:3144701:G:C	R200T	0.997
3:3144710:G:C	R203T	0.997
3:3148092:T:A	W415R	0.997

dbSNP variants (sampled 300 via entrez): RS1000026694 (3:3138190 G>T), RS1000034275 (3:3145435 G>A), RS1000046424 (3:3134598 T>C,G), RS1000059227 (3:3128579 A>G), RS1000079919 (3:3150141 T>C,G), RS1000130651 (3:3127601 TG>T), RS1000223521 (3:3143230 C>G), RS1000337613 (3:3147765 A>G), RS1000453634 (3:3147996 A>T), RS1000528550 (3:3149078 T>G), RS1000601677 (3:3148106 T>C), RS1000707944 (3:3143403 T>G), RS1000716506 (3:3129052 C>A,T), RS1000822511 (3:3125213 G>A,T), RS1000876521 (3:3134683 A>C)

Disease associations

OMIM: gene MIM:612907 | disease phenotypes: MIM:616084, MIM:616959, MIM:607417, MIM:617771

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome	Strong	Autosomal recessive
retinitis pigmentosa and erythrocytic microcytosis	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome	Definitive	AR

Mondo (7): congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (MONDO:0014487), retinitis pigmentosa and erythrocytic microcytosis (MONDO:0014850), inherited retinal dystrophy (MONDO:0019118), intellectual disability, autosomal recessive 2 (MONDO:0011828), developmental and epileptic encephalopathy, 57 (MONDO:0033366), optic atrophy (MONDO:0003608), fetal growth restriction (MONDO:0005030)

Orphanet (3): Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (Orphanet:369861), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Autosomal recessive non-syndromic intellectual disability (Orphanet:88616)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001334	Communicating hydrocephalus
HP:0001510	Growth delay
HP:0001638	Cardiomyopathy
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001981	Schistocytosis
HP:0002059	Cerebral atrophy
HP:0002188	Delayed CNS myelination
HP:0002194	Delayed gross motor development
HP:0002299	Brittle hair
HP:0003128	Lactic acidosis
HP:0003355	Aminoaciduria
HP:0003593	Infantile onset
HP:0003621	Juvenile onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002382_98	Eosinophil percentage of white cells	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D005317	Fetal Growth Retardation	C12.050.703.277.370; C16.300.390; C23.550.393.450
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C564404	Mental Retardation, Autosomal Recessive 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
bisphenol S	increases expression, increases methylation	2
Air Pollutants	increases abundance, decreases expression, affects expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	decreases expression	1
tobacco tar	decreases expression	1
manganese chloride	increases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression	1
Ozone	increases abundance, affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

273 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00347867	PHASE4	UNKNOWN	Viagra for the Treatment of IUGR
NCT00909974	PHASE4	COMPLETED	Effect of Prenatal Nutritional Supplementation on Birth Outcome in Hounde District, Burkina Faso
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01390051	PHASE4	COMPLETED	Can Low Molecular Weight Heparin During Pregnancy With Intrauterine Growth Restriction Increase Birth Weight?
NCT01695070	PHASE4	COMPLETED	Melatonin to Prevent Brain Injury in Unborn Growth Restricted Babies
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT05029778	PHASE4	UNKNOWN	Arginine + Citrulline as a Supplement for Weight Gain in Fetus With a Decrease in Their Growth Curve
NCT05800938	PHASE4	COMPLETED	The Effect of Oral Isosorbide Mononitrate Therapy on Umbilical Artery Doppler Resistance Index in Pregnancies With Intrauterine Growth Restriction: Prospective Randomized Control Trial
NCT07171086	PHASE4	NOT_YET_RECRUITING	AI-POCUS for Maternal and Neonatal Health in Ethiopia
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00174252	PHASE3	COMPLETED	Study Aimed At Improving Height With Genotonorm In Children Born Little And/Or Light With Growth Retardation At The Age
NCT00197340	PHASE3	COMPLETED	Antepartum Chronic Epidural Therapy (ACET) to Improve Blood Flow to the Uterus, Placenta and Baby in Pre-Eclampsia and Intrauterine Growth Restriction
NCT00452491	PHASE3	COMPLETED	MAXOMAT ® in the Treatment of Severe Early Onset Intrauterine Growth Retardation on Pre-pubertal Children
NCT01073605	PHASE3	COMPLETED	Genotropin Treatment in Short Prepubertal Children With Intra-Uterine Growth Retardation
NCT02336243	PHASE3	UNKNOWN	A Randomized Trial of Docosahexaenoic Acid Supplementation During Pregnancy to Prevent Deep Placentation Disorders
NCT02590536	PHASE3	COMPLETED	A Trial Evaluating the Role of Sildenafil in the Treatment of Fetal Growth Restriction
NCT02672566	PHASE3	COMPLETED	Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction
NCT03177824	PHASE3	UNKNOWN	Sildenafil Citrate for Treatment of Growth-restricted Fetuses
NCT03230162	PHASE3	UNKNOWN	Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment
NCT03324139	PHASE3	COMPLETED	Treatment of Intrauterine Growth Restriction With Low Molecular Heparin.
NCT03669185	PHASE3	UNKNOWN	Pentaerithrityl Tetranitrate (PETN) for Secondary Prevention of Intrauterine Growth Restriction
NCT04084990	PHASE3	TERMINATED	Sleep Apnea and Fetal Growth Restriction
NCT04356326	PHASE3	RECRUITING	Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy
NCT04557475	PHASE3	WITHDRAWN	Transplacental Aspirin Therapy for Early Onset Fetal Growth Restriction
NCT04762992	PHASE3	ENROLLING_BY_INVITATION	LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)
NCT05253781	PHASE3	COMPLETED	Low Dose Aspirin for Preventing Intrauterine Growth Restriction and Preeclampsia in Sickle Cell Pregnancy (PIPSICKLE)
NCT05651347	PHASE3	RECRUITING	Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction
NCT05774236	PHASE3	COMPLETED	Cook´s Balloon Versus Dinoprostone for Labor Induction of Term Pregnancies With Fetal Growth Restriction
NCT06497959	PHASE3	RECRUITING	Study of Placental Vascularization Using Contrast Ultrasound
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02280031	PHASE2	COMPLETED	Effect of Low Dose Aspirin on Birthweight in Twins: The GAP Trial.
NCT02425436	PHASE2	COMPLETED	Role of Ginkgo Biloba Extract in IUGR
NCT02678221	PHASE2	UNKNOWN	Sildenafil Citrate for the Management of Asymmetrical Intrauterine Growth Restriction
NCT02696577	PHASE2	COMPLETED	The Effect of Omega 3 on Pregnancy Complicated by Asymmetrical Intrauterine Growth Restriction
NCT07098975	PHASE2	RECRUITING	Statin Intervention for Severe Early-Onset Placental Insufficiency. (STATIN-PRE Trial)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects