ITPA

protein-coding

inosine triphosphatase

Gene summary

This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

Previous symbols:

C20orf37

MANE transcript

NM_033453.4

Inheritance

ClinVar variants

P:46U:107B:75

Top phenotype

Inosine triphosphatase deficiency

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr20:3,208,868-3,223,870

External References & Databases

Ensembl (ENSG00000125877)

Transcript & Mutation Effects

hg38 • Region Span ~15.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

*ITPA* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2015 (Kevelam et al., PMID: 26224535). Developmental and epileptic encephalopathy (DEE) is a neurodevelopmental disorder characterized by onset of seizures early in life along with delays in development. Other individuals with monoallelic or biallelic variants in *ITPA* may present with inosine triphosphate pyrophosphohydrolase (ITPase) deficiency, which is a common condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes (PMIDs: 12436200, 12384777). These patients are otherwise asymptomatic and do not present with any developmental delays nor with epilepsy. When evaluating these conditions, we found differences in inheritance pattern between individuals with DEE and individuals with isolated ITPase deficiency; individuals with ITPase deficiency may have monoallelic or biallelic variants, whereas individuals with DEE presented solely with biallelic ITPA variants. Additionally, we found a strong difference in phenotypic variability between these patients. Individuals reported with isolated ITPase deficiency were asymptomatic, whereas DEE is an often severe neurodevelopmental disorder with childhood onset. Currently, the molecular mechanism underlying these different phenotypic presentations is not well understood. However, the current hypothesis is that DEE is the result of putative loss of function or destruction of crucial binding sites (PMID: 34989426). Therefore, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have decided to split these disease assertions and will not be including individuals with isolated ITPase deficiency in this curation for DEE. Six variants (nonsense, frameshift, splice site, missense, single exon deletion) that have been reported in seven probands in three publications are included in this curation (PMIDs: 26224535, 34989426, 33593863). In addition to epilepsy and developmental delays, patients commonly present with microcephaly and hypotonia. Patients may also exhibit delayed myelination and mild to moderate cerebral atrophy on brain MRIs. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between ITPA and autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date February 6, 2024 (SOP Version 10).

developmental and epileptic encephalopathy, 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014719

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 35SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014719

Submitter: Orphanet

inosine triphosphatase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013461

Submitter: Ambry Genetics

inosine triphosphatase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013461

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014719

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Inosine triphosphatase deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: Pharmacogenomic

Rationale: Abnormal 6-mercaptopurine metabolism in ITPase-deficient patients may cause thiopurine drug toxicity

Refs: 1204209; 12384777; 17697198; 19214663; 19631656; 19682085; 26224535

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITPA variants in ClinVar

9 Conditions Cataloged

Inosine triphosphatase deficiencyTotal: 261

Developmental and epileptic encephalopathy, 35Total: 41

not providedTotal: 38

Inborn genetic diseasesTotal: 20

ITPA-related disorderTotal: 6

not specifiedTotal: 5

Infantile epileptic dyskinetic encephalopathyTotal: 3

HypodontiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033453.4. 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			2 clinvar	69 clinvar	1 clinvar	72
missense		6 clinvar	99 clinvar	4 clinvar	1 clinvar	110
nonsense	6 clinvar	5 clinvar				11
start loss			2 clinvar			2
frameshift	8 clinvar	4 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)	8 clinvar	9 clinvar	2 clinvar			19
Total	22	24	107	73	2	228

Highest pathogenic variant AF is 0.000043995104

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033453.4	RefSeq	NP_258412.1	8	MANE Select
ENST00000380113.8	Ensembl	ENSP00000369456.3	8	MANE Select
NM_001267623.2	RefSeq	NP_001254552.1	6	Standard
NM_001324236.2	RefSeq	NP_001311165.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Drug metabolism - other enzymes - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics
Purine Nucleoside Phosphorylase Deficiency
Mercaptopurine Action Pathway

Biological Process

ITP catabolic process
purine nucleotide catabolic process
nucleoside triphosphate catabolic process
deoxyribonucleoside triphosphate catabolic process
chromosome organization

Molecular Function

nucleotide binding
NADH pyrophosphatase activity
dITP diphosphatase activity
ITP diphosphatase activity
XTP diphosphatase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380113
Coding exons: 8
Length: 15003
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.123	111	115	0.968	0.00000672	1243
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.469

Intolerance Scores

LoFtool: 0.304
RVIS EVS: 0.06
RVIS percentile EVS: 58.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0873

Gene Damage Prediction

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