NUDT15
protein-codingnudix hydrolase 15, the group of Nudix hydrolase family
Gene summary
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Apr 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
Clinical Genomic Database (CGD)
Manifestation: General
Intervention: Pharmacogenomic
Rationale: Individuals have been reported as having severe hematopoietic toxicity when treated with standard doses of thiopurines, and awareness may allow adjustments to the medication regimen
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NUDT15 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018283.4. 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 | 4 | 4 | ||||
| missense | 14 | 1 | 15 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 16 | 5 | 0 | 21 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060753.1 | 3 | MANE Select | |
| Ensembl | ENSP00000258662.1 | 3 | MANE Select | |
| RefSeq | NP_001291674.1 | 2 | Standard | |
| Ensembl | ENSP00000545762.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Nucleobase catabolism
- Metabolism of nucleotides
- Metabolism
- Phosphate bond hydrolysis by NUDT proteins
- Purine catabolism
Biological Process
- mitotic cell cycle
- purine nucleotide catabolic process
- dGTP catabolic process
- nucleobase-containing small molecule catabolic process
- DNA protection
Molecular Function
- protein binding
- 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity
- nucleoside-diphosphatase activity
- NADH pyrophosphatase activity
- 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity
Cellular Component
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000258662
- Coding exons
- 3
- Length
- 9656
- Individuals with no LoFs
- 125588
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 160
- Defined
- 125748
- p
- 0.000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0677 | 83 | 84.8 | 0.979 | 0.00000370 | 1049 |
| Missense (PolyPhen) | 24 | 29.278 | 0.81973 | 376 | ||
| Synonymous | -0.499 | 35 | 31.4 | 1.11 | 0.00000137 | 310 |
| Loss of Function | 0.815 | 5 | 7.39 | 0.677 | 3.14e-7 | 89 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00014 | 0.00012 | rare |
| Latino/Admixed American | 0.00018 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0.0058 | 0.0051 | notable |
| European (Non-Finnish) | 0.00028 | 0.00024 | rare |
| South Asian | 0.00030 | 0.00029 | rare |
| Other | 0.00053 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May catalyze the hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP and the prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP (PubMed:26238318). Could also catalyze the hydrolysis of some nucleoside diphosphate derivatives (PubMed:22556419, PubMed:26238318). Hydrolyzes oxidized nucleosides triphosphates like 8-oxo-dGTP in vitro, but the specificity and efficiency towards these substrates are low. Therefore, the potential in vivo sanitizing role of this enzyme, that would consist in removing oxidatively damaged forms of nucleosides to prevent their incorporation into DNA, is unclear (PubMed:26238318, PubMed:22556419). Through the hydrolysis of thioguanosine triphosphates may participate in the catabolism of thiopurine drugs (PubMed:26238318, PubMed:25108385). May also have a role in DNA synthesis and cell cycle progression by stabilizing PCNA (PubMed:19419956). {ECO:0000269|PubMed:19419956, ECO:0000269|PubMed:22556419, ECO:0000269|PubMed:25108385, ECO:0000269|PubMed:26238318}.;
Intolerance Scores
- LoFtool
- 0.755
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 56.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.508
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |