GeneBe

TRNT1

protein-coding

tRNA nucleotidyl transferase 1

Gene summary

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. [provided by RefSeq, Dec 2014]

MANE transcript

NM_182916.3

Inheritance

AR

ClinVar variants

P:89U:282B:127

Top phenotype

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr3:3,126,933-3,153,435

External References & Databases

Ensembl (ENSG00000072756)NCBI Gene (51095)OMIM (612907)HGNC:17341GenCCUniProt (Q96Q11)AlphaFoldClinVar (TRNT1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~26.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa and erythrocytic microcytosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014850

Submitter: Labcorp Genetics (formerly Invitae)

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014487

Submitter: Orphanet

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014487

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014487

Submitter: PanelApp Australia

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014487

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa and erythrocytic microcytosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014850

Submitter: G2P

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014487

Submitter: ClinGen

Per Criteria outlined by the ClinGen Lumping and Splitting working group, we found no difference in molecular mechanism or inheritance pattern underlying the disease entities: (1) Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), (MIM:616084) and (2) Retinitis pigmentosa and erythrocytic microcytosis, (MIM:616959). Therefore, evidence favor lumping the entities (MIM:616084 and MIM:616959) to a single disease spectrum. TRNT1 (CCA-adding tRNA nucleotidyl transferase enzyme) performs an essential post- transcriptional modification by adding on the cytosine- cytosine-adenine (CCA) trinucleotide sequence to the 3′ end of all newly produced tRNAs. This TRNT1- dependent tRNA modification is essential for both cytosolic and mitochondrial tRNAs (mt-tRNAs) to participate in protein biosynthesis. Mutations in *TRNT1* were first reported to cause a syndrome characterized by congenital sideroblastic anemia, B-cell immunodeficiency, recurrent fevers and developmental delay (referred to as SIFD) in 2014 (PMID: 25193871). Retinitis pigmentosa and erythrocytic microcytosis were also reported in SIFD patients (PMID: 27370603). 2 frameshift , 2 splicing , and 3 missense TRNT1 variants are used in this curation. Mechanism of pathogenicity seems to be loss of function resulting in impaired ability of TRNT1 to catalyze the formation of the CCA trinucleotide (PMID: 25193871) Experimental evidence also supports this gene-disease relationship. Phenotypes of the lumped diseases could be recapitulated in Zebrafish model system through the same molecular pathway. Morphological analysis of the MO-injected embryos (morphants) revealed cardiovascular defects and reduced eye size in addition to reduced staining of hemoglobin-containing red blood cells and significantly reduced touch response. RNA sequencing confirmed that Morphants had a significantly lower CCA incorporation efficiency than controls (PMID: 26494905). Mt-tRNAs lacking CCA are also detected in patients’ fibroblasts compared to controls (PMID: 27370603). In summary, *TRNT1* is definitively associated with the disease spectrum Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) and Retinitis pigmentosa and erythrocytic microcytosis. 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 Antibody Deficiencies GCEP on October 7, 2022.

Clinical Genomic Database (CGD)

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delayAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Hematologic; Neurologic; Ophthalmologic; Renal

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Hematologic

Rationale: Medical management (with immunoglobulin therapy) has been described as beneficial; Most patients have been described as requiring regular blood transfusions for treatment of anemia, as well as iron chelation; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; BMT has been described

Refs: 25193871; 26494905Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRNT1 variants in ClinVar

10 Conditions Cataloged
Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndromeTotal: 522
not providedTotal: 88
Inborn genetic diseasesTotal: 75
not specifiedTotal: 39
Retinal dystrophyTotal: 24
Retinitis pigmentosa and erythrocytic microcytosisTotal: 23
TRNT1-related disorderTotal: 20
Developmental and epileptic encephalopathy, 57Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182916.3. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
113
clinvar
1
clinvar
 120
missense
4
clinvar
8
clinvar
266
clinvar
11
clinvar
1
clinvar
 290
nonsense
9
clinvar
4
clinvar
1
clinvar
 14
start loss
1
clinvar
 1
frameshift
44
clinvar
12
clinvar
3
clinvar
1
clinvar
 60
splice donor/acceptor (+/-2bp)
2
clinvar
6
clinvar
5
clinvar
 13
Total59302821252498

Highest pathogenic variant AF is 0.00024112935

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 75 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_182916.3RefSeqNP_886552.37MANE Select
ENST00000251607.11EnsemblENSP00000251607.67MANE Select
NM_001302946.2RefSeqNP_001289875.27Standard
NM_001367321.1RefSeqNP_001354250.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
trnt1Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • RNA transport - Homo sapiens (human)
  • tRNA processing
  • Metabolism of RNA
  • tRNA processing in the mitochondrion
  • tRNA processing in the nucleus

Biological Process

  • tRNA 3'-terminal CCA addition
  • tRNA 3'-end processing
  • mitochondrial tRNA 3'-end processing

Molecular Function

  • tRNA binding
  • ATP binding
  • 5'-3' RNA polymerase activity
  • CTP:tRNA cytidylyltransferase activity
  • CTP:3'-cytidine-tRNA cytidylyltransferase activity

Cellular Component

  • nucleoplasm
  • mitochondrion
  • mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000251607
Coding exons
7
Length
23964
Individuals with no LoFs
125615
Homozygous LoFs
0
Heterozygous LoFs
133
Defined
125748
p
0.000529
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.152732251.220.00001092865
Missense (PolyPhen)8172.5141.117874
Synonymous0.2447678.80.9650.00000390786
Loss of Function1.95917.90.5027.48e-7255

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000380.00037rare
Latino/Admixed American0.000630.00061rare
Ashkenazi Jewish00.0absent
East Asian0.000510.00049rare
Finnish0.000380.00037rare
European (Non-Finnish)0.000710.00069rare
South Asian0.000390.00036rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Isoform 1: Adds and repairs the conserved 3'-CCA sequence necessary for the attachment of amino acids to the 3' terminus of tRNA molecules, using CTP and ATP as substrates. {ECO:0000269|PubMed:11504732}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:25193871}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:26494905}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.115

Intolerance Scores

LoFtool
0.899
RVIS EVS
-0.6
RVIS percentile EVS
17.91

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.808

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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