NSUN3
protein-codingNOP2/Sun RNA methyltransferase 3, the group of NOP2/Sun RNA methyltransferase family
Gene summary
Enables tRNA (cytidine-N5)-methyltransferase activity. Involved in regulation of mitochondrial translation and tRNA wobble base cytosine methylation. Located in mitochondrial matrix. Implicated in combined oxidative phosphorylation deficiency 48. [provided by Alliance of Genome Resources, Jun 2026]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~68.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0033566
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0033566
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NSUN3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022072.5. 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 | 27 | 1 | 28 | |||
| missense | 2 | 78 | 5 | 1 | 86 | |
| nonsense | 1 | 1 | 3 | 5 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 7 | |||
| Total | 4 | 2 | 88 | 32 | 2 | 128 |
Highest pathogenic variant AF is 0.00008801835
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071355.1 | 6 | MANE Select | |
| Ensembl | ENSP00000318986.4 | 6 | MANE Select | |
| Ensembl | ENSP00000419297.1 | 4 | Standard | |
| Ensembl | ENSP00000645984.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- tRNA wobble base cytosine methylation
- rRNA methylation
- regulation of mitochondrial translation
Molecular Function
- tRNA binding
- methyltransferase activity
- tRNA (cytosine-5-)-methyltransferase activity
Cellular Component
- mitochondrion
- mitochondrial matrix
- mitochondrial large ribosomal subunit
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000314622
- Coding exons
- 6
- Length
- 65630
- Individuals with no LoFs
- 125702
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 45
- Defined
- 125747
- p
- 0.000179
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.306 | 164 | 175 | 0.935 | 0.00000842 | 2200 |
| Missense (PolyPhen) | 64 | 66.343 | 0.96468 | 845 | ||
| Synonymous | 0.920 | 58 | 67.6 | 0.858 | 0.00000347 | 657 |
| Loss of Function | 0.668 | 14 | 17.0 | 0.825 | 9.51e-7 | 202 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00062 | 0.00062 | rare |
| Latino/Admixed American | 0.00031 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mitochondrial tRNA methyltransferase that mediates methylation of cytosine to 5-methylcytosine (m5C) at position 34 of mt-tRNA(Met) (PubMed:27497299, PubMed:27214402, PubMed:27356879). mt-tRNA(Met) methylation at cytosine(34) takes place at the wobble position of the anticodon and initiates the formation of 5-formylcytosine (f(5)c) at this position (PubMed:27497299, PubMed:27214402, PubMed:27356879). mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation (PubMed:27497299, PubMed:27356879). {ECO:0000269|PubMed:27214402, ECO:0000269|PubMed:27356879, ECO:0000269|PubMed:27497299}.;
- Disease
- DISEASE: Note=Mitochondrial complex deficiency (PubMed:27356879). A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected (PubMed:27356879). Clinical features include combined developmental disability, microcephaly, failure to thrive, recurrent increased lactate levels in plasma, muscular weakness, proximal accentuated, external ophthalmoplegia and convergence nystagmus (PubMed:27356879). Defects are probably caused by deficient methylation and formylation of mt-tRNA(Met) wobble cytosine (PubMed:27356879). The disease may be caused by mutations affecting the gene represented in this entry. {ECO:0000269|PubMed:27356879}.;
Recessive Scores
- pRec
- 0.0960
Intolerance Scores
- LoFtool
- 0.830
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 37.11
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.892
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |