NUDT15

Chr 13AD

nudix hydrolase 15

Also known as: MTH2, NUDT15D

NCBI Gene: 55270 ENSG00000136159 UniProt: Q9NV35 OMIM: 615792

The enzyme catalyzes hydrolysis of nucleoside triphosphates including thiopurine drug derivatives like 6-thio-dGTP and 6-thio-GTP, serving as a negative regulator of thiopurine activation and toxicity. Mutations cause poor metabolism of thiopurines with autosomal dominant inheritance, leading to thiopurine-induced early leukopenia in patients receiving these medications. This gene shows low constraint against loss-of-function variants, indicating tolerance to such mutations in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Thiopurines, poor metabolism of, 2}MIM #616903

Active trials

107

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.41

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.41LOEUF

pLI 0.002

Z-score 0.81

OE 0.68 (0.35–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.07Z-score

OE missense 0.98 (0.82–1.18)

83 obs / 84.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.35–1.41)

0≤0.351.4

Missense OE?0.98 (0.82–1.18)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 5 / 7.4Missense obs/exp: 83 / 84.8Syn Z: -0.50

Background carrier burden — how many people carry a rare variant somewhere in NUDT15?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

234 rare PASS variants

Rare truncating (LoF)

1 in 620

64 rare PASS variants

Rare synonymous (reference)

1 in 1,400

91 rare PASS variants

Rare missense and truncating variants are carried at similar rates in NUDT15; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 380	1 in 900
South Asian	~43k	1 in 180	1 in 1,200
Remaining (unassigned)	~30k	1 in 190	1 in 460
European (Finnish)	~27k	1 in 2,200	none seen
Admixed American	~22k	1 in 260	1 in 1,800
African / African American	~21k	1 in 170	1 in 1,200
East Asian	~20k	1 in 360	1 in 3,300
Ashkenazi Jewish	~13k	1 in 430	none seen
Middle Eastern	~2,884	1 in 360	≈ 1 in 1,100

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓