GeneBe

HPRT1

protein-coding

hypoxanthine phosphoribosyltransferase 1

Gene summary

The protein encoded by this gene is a transferase, which catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate. This enzyme plays a central role in the generation of purine nucleotides through the purine salvage pathway. Mutations in this gene result in Lesch-Nyhan syndrome or gout.[provided by RefSeq, Jun 2009]

Previous symbols:
  • HPRT

MANE transcript

NM_000194.3

Inheritance

XL

ClinVar variants

P:114U:106B:36

Top phenotype

Hyperuricemia, HPRT related (Kelley-Seegmiller syndrome); Lesch-Nyhan syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:134,460,165-134,520,513

External References & Databases

Ensembl (ENSG00000165704)NCBI Gene (3251)OMIM (308000)HGNC:5157GenCCUniProt (P00492)AlphaFoldClinVar (HPRT1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~60.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lesch-Nyhan syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: Orphanet

hypoxanthine guanine phosphoribosyltransferase partial deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010299

Submitter: PanelApp Australia

Lesch-Nyhan syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: Labcorp Genetics (formerly Invitae)

Lesch-Nyhan syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: PanelApp Australia

hypoxanthine guanine phosphoribosyltransferase partial deficiencySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010299

Submitter: Orphanet

Lesch-Nyhan syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: ClinGen

*HPRT1* was first reported in relation to X-linked Lesch-Nyhan syndrome in 1989 (PMID: 2928313). *HPRT1* encodes a transferase involved in purine nucleotide generation in the purine salvage pathway. Lesch-Nyhan syndrome is characterized by intellectual disability, spastic cerebral palsy, choreoathetosis, urinary stones, and destructive biting behaviors. Nine unique variants (nonsense, frameshift, and missense) that have been reported in 10 probands in 5 publications (PMIDs: 8664901, 10767182, 2323782, 23975452, 2928313) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including expression evidence, functional alteration studies, and a mouse model (PMIDs: 24206569, 28495876, 3029599). In summary, there is definitive evidence supporting the relationship between *HPRT1* and X-linked Lesch-Nyhan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene was originally curated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 7, 2018 (SOP Version 5). As of July 8, 2022, this record underwent a recuration of evidence and remains at a definitive classification (SOP Version 9).

hypoxanthine guanine phosphoribosyltransferase partial deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010299

Submitter: Labcorp Genetics (formerly Invitae)

Lesch-Nyhan syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: G2P

Lesch-Nyhan syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: Natera

Lesch-Nyhan syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010298

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hyperuricemia, HPRT related (Kelley-Seegmiller syndrome); Lesch-Nyhan syndromeXL

Manifestation: Biochemical; Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical; Renal

Rationale: Treatments related to uric acid overproduction, such as alkalinization and allopurinol, can be effective in order to prevent and treat sequelae such as renal dysfunction and gouty arthritis

Comments: In Lesch-Nyhan syndrome, an allelic condition, as in Kelley-Seegmiller syndrome, control of uric acid production can be effective to reduce sequelae, but does not affect Neurological manifestations

Refs: 14142409; 4291947; 4322125; 3600927; 10657589; 11891689; 20301328; 20558399; 31182398Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HPRT1 variants in ClinVar

38 Conditions Cataloged
Lesch-Nyhan syndromeTotal: 209
Partial hypoxanthine-guanine phosphoribosyltransferase deficiencyTotal: 176
not providedTotal: 66
HPRT1-related disorderTotal: 20
not specifiedTotal: 16
Nephrolithiasis/nephrocalcinosisTotal: 10
Lesch-nyhan syndrome, neurologic variantTotal: 2
HPRT YALETotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000194.3. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
30
clinvar
4
clinvar
 43
missense
36
clinvar
23
clinvar
77
clinvar
1
clinvar
 137
nonsense
8
clinvar
2
clinvar
6
clinvar
 16
start loss
2
clinvar
1
clinvar
 3
frameshift
18
clinvar
4
clinvar
2
clinvar
 24
splice donor/acceptor (+/-2bp)
16
clinvar
4
clinvar
12
clinvar
1
clinvar
 33
Total8034106324256

Highest pathogenic variant AF is 0.0000019770464

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000194.3RefSeqNP_000185.19MANE Select
ENST00000298556.8EnsemblENSP00000298556.79MANE Select
ENST00000883913.1EnsemblENSP00000553972.17Standard
ENST00000883913.2EnsemblENSP00000553972.17Standard

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

  • T cell mediated cytotoxicity
  • response to amphetamine
  • purine nucleotide biosynthetic process
  • purine ribonucleoside salvage
  • adenine salvage

Molecular Function

  • nucleotide binding
  • magnesium ion binding
  • hypoxanthine phosphoribosyltransferase activity
  • protein binding
  • identical protein binding

Cellular Component

  • cytoplasm
  • cytosol
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000298556
Coding exons
9
Length
60361
Individuals with no LoFs
122217
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
122218
p
0.00000409
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.322077.40.2580.000005241444
Missense (PolyPhen)219.1470.10445395
Synonymous1.621525.40.5910.00000167397
Loss of Function2.7508.790.006.70e-7169

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000370.000030rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5- phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.;
Disease
DISEASE: Lesch-Nyhan syndrome (LNS) [MIM:300322]: Characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self- mutilation. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:20544509, ECO:0000269|PubMed:2071157, ECO:0000269|PubMed:2246854, ECO:0000269|PubMed:2347587, ECO:0000269|PubMed:2358296, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2572141, ECO:0000269|PubMed:2910902, ECO:0000269|PubMed:3265398, ECO:0000269|PubMed:3384338, ECO:0000269|PubMed:6853716, ECO:0000269|PubMed:7627191, ECO:0000269|PubMed:9452051}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gout HPRT-related (GOUT-HPRT) [MIM:300323]: Characterized by partial enzyme activity and hyperuricemia. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:20544509, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2896620, ECO:0000269|PubMed:2909537, ECO:0000269|PubMed:3198771, ECO:0000269|PubMed:3358423, ECO:0000269|PubMed:6572373, ECO:0000269|PubMed:6706936, ECO:0000269|PubMed:6853490, ECO:0000269|PubMed:7987318}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.941

Intolerance Scores

LoFtool
0.128
RVIS EVS
-0.01
RVIS percentile EVS
52.85

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.445

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumLowLow
Primary ImmunodeficiencyMediumLowMedium
CancerMediumLowMedium
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