ITPA

Chr 20AR

inosine triphosphatase

ENSG00000125877 UniProt: Q9BY32 OMIM: 147520

The encoded protein functions as an inosine triphosphate pyrophosphohydrolase that hydrolyzes inosine triphosphate and deoxyinosine triphosphate to monophosphate nucleotides and diphosphate in the cytoplasm. Mutations cause autosomal recessive inosine triphosphatase deficiency, which leads to ITP accumulation in red blood cells, and developmental and epileptic encephalopathy 35. The pathogenic mechanism appears to involve dominant-negative effects of mutant proteins.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.352 OMIM phenotypes

Clinical Summary— ITPA

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.35LOEUF

pLI 0.000

Z-score 0.58

OE 0.84 (0.53–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.12Z-score

OE missense 0.97 (0.83–1.13)

111 obs / 114.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.53–1.35)

0≤0.351.4

Missense OE?0.97 (0.83–1.13)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 12 / 14.4Missense obs/exp: 111 / 114.7Syn Z: -0.45

This gene — mechanism propensity

0.6743th %ile

GOF

0.3689th %ile

LOF

0.3066th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.