ITPA

inosine triphosphatase

Basic information

Region (hg38): 20:3208867-3223870

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
• 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 (233 variants)
• not provided (40 variants)
• Developmental and epileptic encephalopathy, 35 (19 variants)
• Inborn genetic diseases (9 variants)
• not specified (5 variants)
• peginterferon alfa-2b and ribavirin response - Toxicity (2 variants)
• ITPA-related condition (2 variants)
• Inosine triphosphatase deficiency;Developmental and epileptic encephalopathy, 35 (1 variants)
• Infantile epileptic dyskinetic encephalopathy (1 variants)
• Partial congenital absence of teeth (1 variants)
• Seizure;Intellectual disability (1 variants)
• Developmental and epileptic encephalopathy, 35;Inosine triphosphatase deficiency (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	49	4	55
missense		1	88	3	1	93
nonsense	4	2				6
start loss			1			1
frameshift	3	3	1			7
inframe indel						0
splice donor/acceptor (+/-2bp)	2	9				11
splice region			13	12	2	27
non coding			2	43	14	59
Total	9	15	94	95	19

Highest pathogenic variant AF is 0.0000131

Variants in ITPA

This is a list of pathogenic ClinVar variants found in the ITPA region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-3209336-G-A			Benign (May 12, 2021)
20-3209393-C-G			Benign (May 13, 2021)
20-3209439-C-T			Benign (May 26, 2021)
20-3209552-A-G		Inosine triphosphatase deficiency	Uncertain significance (Jan 11, 2022)
20-3209556-C-A		Inosine triphosphatase deficiency	Uncertain significance (Jul 15, 2021)
20-3209557-G-T		Inosine triphosphatase deficiency	Likely benign (Jan 02, 2024)
20-3209560-C-T		Inosine triphosphatase deficiency	Likely benign (Jul 26, 2022)
20-3209564-T-C		Inosine triphosphatase deficiency	Likely benign (May 16, 2023)
20-3209585-T-C		Inosine triphosphatase deficiency	Uncertain significance (Dec 11, 2023)
20-3209593-G-C		Inosine triphosphatase deficiency	Likely benign (Oct 09, 2020)
20-3209598-ACGCCAAGAAGCTGGAGGAGGTG-A		Inosine triphosphatase deficiency	Likely pathogenic (Feb 13, 2020)
20-3209599-C-T		Inosine triphosphatase deficiency	Likely benign (Mar 14, 2019)
20-3209600-G-T		Inosine triphosphatase deficiency	Likely benign (Nov 27, 2023)
20-3209608-GC-AA		Inosine triphosphatase deficiency	Uncertain significance (Sep 06, 2022)
20-3209609-C-A		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
20-3209617-G-A		Inosine triphosphatase deficiency	Uncertain significance (Jun 27, 2022)
20-3209620-G-C		Developmental and epileptic encephalopathy, 35	Uncertain significance (May 20, 2019)
20-3209622-C-T		Inosine triphosphatase deficiency	Uncertain significance (Aug 01, 2022)
20-3209625-G-T		Inosine triphosphatase deficiency	Uncertain significance (Jul 06, 2022)
20-3209627-G-A		Inosine triphosphatase deficiency	Likely benign (Mar 23, 2022)
20-3209627-G-C		Inosine triphosphatase deficiency	Likely benign (Dec 11, 2023)
20-3209627-G-GGGT		Inosine triphosphatase deficiency	Likely benign (Jan 17, 2024)
20-3209632-T-C		Inosine triphosphatase deficiency	Likely benign (Jul 03, 2023)
20-3209633-T-G		Inosine triphosphatase deficiency	Likely benign (Dec 18, 2023)
20-3209634-G-A		Inosine triphosphatase deficiency	Likely benign (Nov 27, 2023)

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
1.01e-7	0.331	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

Haploinsufficiency Scores

• pHI: 0.0526
• hipred: Y
• hipred_score: 0.626
• ghis: 0.473

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

Mouse Genome Informatics

• Gene name: Itpa
• Phenotype: hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

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