ITPA

inosine triphosphatase

Basic information

Region (hg38): 20:3208868-3223870

Previous symbols: [ "C20orf37" ]

Links

ENSG00000125877 ∙ NCBI:3704 ∙ OMIM:147520 ∙ HGNC:6176 ∙ Uniprot:Q9BY32 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 35 (Supportive), mode of inheritance: AR
• genetic developmental and epileptic encephalopathy (Definitive), mode of inheritance: AR
• inosine triphosphatase deficiency (Moderate), mode of inheritance: AR
• developmental and epileptic encephalopathy, 35 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Inosine triphosphatase deficiency	AR	Pharmacogenomic	Abnormal 6-mercaptopurine metabolism in ITPase-deficient patients may cause thiopurine drug toxicity	Biochemical; Neurologic	1204209; 12384777; 17697198; 19214663; 19631656; 19682085; 26224535

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ITPA gene.

• Inosine_triphosphatase_deficiency (256 variants)
• not_provided (38 variants)
• Developmental_and_epileptic_encephalopathy,_35 (34 variants)
• Inborn_genetic_diseases (20 variants)
• ITPA-related_disorder (6 variants)
• not_specified (4 variants)
• Infantile_epileptic_dyskinetic_encephalopathy (3 variants)
• Hypodontia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ITPA gene is commonly pathogenic or not. These statistics are base on transcript: NM_000033453.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	64	1	67
missense		5	99	4	1	109
nonsense	5	4				9
start loss			1			1
frameshift	6	5	2			13
splice donor/acceptor (+/-2bp)	8	9	2			19
Total	19	23	106	68	2

Highest pathogenic variant AF is 0.000043995104

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ITPA	protein_coding	protein_coding	ENST00000380113	8	15003

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.123	111	115	0.968	0.00000672	1243
Missense in Polyphen		37	50.72	0.7295		548
Synonymous	-0.453	52	48.0	1.08	0.00000302	373
Loss of Function	0.578	12	14.4	0.836	8.34e-7	153

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000211	0.000210
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000272	0.000272
Finnish	0.000419	0.000416
European (Non-Finnish)	0.000168	0.000167
Middle Eastern	0.000272	0.000272
South Asian	0.0000327	0.0000327
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (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. {ECO:0000255|HAMAP-Rule:MF_03148, ECO:0000269|PubMed:17090528}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 35 (EIEE35) [MIM:616647]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE35 is characterized by onset of seizures in the first months of life associated with essentially no normal development. Many patients die in early childhood. {ECO:0000269|PubMed:26224535}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Drug metabolism - other enzymes - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Purine Nucleoside Phosphorylase Deficiency;Mercaptopurine Action Pathway;Azathioprine Action Pathway;Pyrimidine Metabolism;Xanthine Dehydrogenase Deficiency (Xanthinuria);Adenylosuccinate Lyase Deficiency;AICA-Ribosiduria;Thioguanine Action Pathway;Adenine phosphoribosyltransferase deficiency (APRT);Mitochondrial DNA depletion syndrome;Myoadenylate deaminase deficiency;Purine Metabolism;UMP Synthase Deiciency (Orotic Aciduria);MNGIE (Mitochondrial Neurogastrointestinal Encephalopathy);Molybdenum Cofactor Deficiency;Adenosine Deaminase Deficiency;Gout or Kelley-Seegmiller Syndrome;Lesch-Nyhan Syndrome (LNS);Xanthinuria type I;Xanthinuria type II;Beta Ureidopropionase Deficiency;Dihydropyrimidinase Deficiency;Nucleobase catabolism;Metabolism of nucleotides;Metabolism;Purine nucleotides nucleosides metabolism;Pyrimidine nucleotides nucleosides metabolism;Purine catabolism (Consensus)

Recessive Scores

• pRec: 0.469

Intolerance Scores

• loftool: 0.304
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.53

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0873

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Gene ontology

• Biological process: ITP catabolic process;purine nucleotide catabolic process;nucleoside triphosphate catabolic process;deoxyribonucleoside triphosphate catabolic process;chromosome organization
• Cellular component: cytosol
• Molecular function: nucleotide binding;NADH pyrophosphatase activity;dITP diphosphatase activity;ITP diphosphatase activity;XTP diphosphatase activity;identical protein binding;metal ion binding;nucleoside-triphosphate diphosphatase activity