PRPS1

phosphoribosyl pyrophosphate synthetase 1

Basic information

Region (hg38): X:107628428-107651993

Previous symbols: [ "DFN2" ]

Links

ENSG00000147224 ∙ NCBI:5631 ∙ OMIM:311850 ∙ HGNC:9462 ∙ Uniprot:P60891 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hearing loss, X-linked 1 (Strong), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked recessive 5 (Strong), mode of inheritance: XL
• Arts syndrome (Strong), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked recessive 5 (Definitive), mode of inheritance: XLR
• hearing loss, X-linked 1 (Definitive), mode of inheritance: XLR
• phosphoribosylpyrophosphate synthetase superactivity (Definitive), mode of inheritance: XLR
• Arts syndrome (Definitive), mode of inheritance: XLR
• Arts syndrome (Supportive), mode of inheritance: XL
• X-linked nonsyndromic hearing loss (Supportive), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked recessive 5 (Supportive), mode of inheritance: XL
• mild phosphoribosylpyrophosphate synthetase superactivity (Supportive), mode of inheritance: XL
• severe phosphoribosylpyrophosphate synthetase superactivity (Supportive), mode of inheritance: XL
• X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome (Supportive), mode of inheritance: XL
• PRPS1 deficiency disorder (Definitive), mode of inheritance: XL
• Arts syndrome (Definitive), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked recessive 5 (Definitive), mode of inheritance: XL
• hearing loss, X-linked 1 (Definitive), mode of inheritance: XL
• phosphoribosylpyrophosphate synthetase superactivity (Definitive), mode of inheritance: XL
• Arts syndrome (Strong), mode of inheritance: XL
• phosphoribosylpyrophosphate synthetase superactivity (Strong), mode of inheritance: XL
• phosphoribosylpyrophosphate synthetase superactivity (Limited), mode of inheritance: XL
• PRPS1 deficiency disorder (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Arts syndrome; Deafness, X-linked 1; Phosphoribosylpyrophosphate synthetase I superactivity	XL	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Renal	In Arts syndrome, treatment with S-adenosylmethionine may be beneficial, and due to infectious risk, prophylaxis and early and aggressive treatment of infections may decrease related morbidity and mortality; Several PRPS1-related conditions can include deafness, which can be congenital/prelingual, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In Phosphoribosylpyrophosphate synthetase I superactivity, medical treatment of uric acid overproduction can be beneficial	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Hematologic; Neurologic; Renal	6069085; 5782823; 171280; 6243137; 3017368; 8498830; 8253776; 7593598; 8882866; 8968763; 10503584; 15240907; 5955956; 17701896; 17701900; 20380929; 20021999; 20301738; 22246954; 24528855; 25182139

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PRPS1 gene.

• Charcot-Marie-Tooth Neuropathy X (5 variants)
• Charcot-Marie-Tooth disease X-linked recessive 5 (2 variants)
• Hearing loss, X-linked 1 (2 variants)
• Arts syndrome (1 variants)
• not provided (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRPS1 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			1	94	4	99
missense	5	15	62	1		83
nonsense	1					1
start loss						0
frameshift	2		1			3
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1		1			2
splice region				13	1	14
non coding			17	40	15	72
Total	9	15	84	135	19

Variants in PRPS1

This is a list of pathogenic ClinVar variants found in the PRPS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-107628475-CG-C		Phosphoribosylpyrophosphate synthetase superactivity • Arts syndrome • Charcot-Marie-Tooth, X-linked • X-linked nonsyndromic hearing loss	Likely benign (Jun 14, 2016)
X-107628581-T-TGCA		not specified	Likely benign (Aug 03, 2016)
X-107628640-C-T		not specified • Charcot-Marie-Tooth Neuropathy X	Benign/Likely benign (May 18, 2023)
X-107628649-C-A			Uncertain significance (Nov 29, 2023)
X-107628652-C-T		Charcot-Marie-Tooth Neuropathy X	Likely benign (Dec 09, 2023)
X-107628653-G-C			Likely pathogenic (Nov 01, 2018)
X-107628655-C-T		Charcot-Marie-Tooth Neuropathy X	Likely benign (Sep 06, 2023)
X-107628667-G-A		Charcot-Marie-Tooth Neuropathy X	Likely benign (Nov 05, 2023)
X-107628671-T-C		Charcot-Marie-Tooth Neuropathy X	Likely benign (Sep 07, 2020)
X-107628674-T-C		Charcot-Marie-Tooth disease X-linked recessive 5	Pathogenic (Sep 23, 2016)
X-107628675-C-T		Retinal dystrophy	Likely pathogenic (Jan 01, 2017)
X-107628682-A-G		Charcot-Marie-Tooth Neuropathy X	Likely benign (Oct 17, 2023)
X-107628688-T-C		Charcot-Marie-Tooth Neuropathy X • Nephrolithiasis/nephrocalcinosis	Likely benign (Jun 28, 2023)
X-107628691-C-T		Charcot-Marie-Tooth Neuropathy X	Likely benign (Jun 15, 2022)
X-107628697-G-A		Charcot-Marie-Tooth Neuropathy X	Likely benign (Jul 16, 2023)
X-107628702-T-C			Likely pathogenic (Jan 01, 2024)
X-107628706-G-A		Charcot-Marie-Tooth Neuropathy X	Likely benign (Dec 13, 2021)
X-107628707-C-T		Charcot-Marie-Tooth Neuropathy X	Likely benign (Nov 03, 2022)
X-107628715-G-A		Charcot-Marie-Tooth Neuropathy X	Likely benign (Aug 07, 2023)
X-107628717-T-A		Charcot-Marie-Tooth Neuropathy X	Uncertain significance (Jun 25, 2022)
X-107628719-GT-G			Uncertain significance (Dec 29, 2017)
X-107628724-T-C		Charcot-Marie-Tooth Neuropathy X	Likely benign (Apr 08, 2022)
X-107628727-G-A		Charcot-Marie-Tooth Neuropathy X	Likely benign (Jun 05, 2021)
X-107628739-C-T		Charcot-Marie-Tooth Neuropathy X	Likely benign (Dec 13, 2021)
X-107628746-A-G			Uncertain significance (May 11, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRPS1	protein_coding	protein_coding	ENST00000372435	7	22520

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.915	0.0841	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.73	10	130	0.0772	0.00000998	2113
Missense in Polyphen		0	34.661	0		573
Synonymous	0.481	41	45.1	0.909	0.00000335	621
Loss of Function	2.61	0	7.94	0.00	5.01e-7	158

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.
• Disease: DISEASE: Note=Phosphoribosyl pyrophosphate synthetase I deficiency is a rare condition caused by mutations in PRPS1 that lead to variable disease phenotypes including optic atrophy, retinitis pigmentosa, ataxia, peripheral neuropathy and hearing loss. {ECO:0000269|PubMed:25491489}.; DISEASE: Phosphoribosylpyrophosphate synthetase superactivity (PRPS1 superactivity) [MIM:300661]: Familial disorder characterized by excessive purine production, gout and uric acid urolithiasis. {ECO:0000269|PubMed:7593598, ECO:0000269|Ref.12}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, X-linked recessive, 5 (CMTX5) [MIM:311070]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy. {ECO:0000269|PubMed:17701900}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: ARTS syndrome (ARTS) [MIM:301835]: A disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Susceptibility to infections, especially of the upper respiratory tract, can result in early death. {ECO:0000269|PubMed:17701896}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, X-linked, 1 (DFNX1) [MIM:304500]: A form of deafness characterized by progressive, severe-to-profound sensorineural hearing loss in males. Females manifest mild to moderate hearing loss. {ECO:0000269|PubMed:20021999}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A mutation in PRPS1 has been found in a patient with a phenotype that bridges that of PRSPS1 superactivity and ARTS syndrome with uric acid overproduction without gout but with recurrent infections, sensorineural hearing loss and motor neuropathy. The intermediate phenotype may be because Leu-142 variant affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss- of-function of PRPP synthetase. {ECO:0000269|PubMed:22246954}.
• Pathway: Purine metabolism - Homo sapiens (human);Pentose phosphate pathway - Homo sapiens (human);Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Nucleotide Metabolism;Pentose phosphate pathway (hexose monophosphate shunt);Metabolism of carbohydrates;PRPP biosynthesis;5-Phosphoribose 1-diphosphate biosynthesis;Metabolism (Consensus)

Recessive Scores

• pRec: 0.292

Intolerance Scores

• rvis_EVS: 0.04
• rvis_percentile_EVS: 56.25

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.572
• ghis: 0.616

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.947

Mouse Genome Informatics

• Gene name: Prps1
• Phenotype: 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); vision/eye phenotype

Zebrafish Information Network

• Gene name: prps1a
• Affected structure: neuromast hair cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: 5-phosphoribose 1-diphosphate biosynthetic process;purine nucleobase metabolic process;purine nucleotide biosynthetic process;pyrimidine nucleotide biosynthetic process;nervous system development;nucleoside metabolic process;ribonucleoside monophosphate biosynthetic process;nucleotide biosynthetic process;phosphorylation;urate biosynthetic process;hypoxanthine biosynthetic process
• Cellular component: ribose phosphate diphosphokinase complex;cytoplasm;cytosol
• Molecular function: magnesium ion binding;ribose phosphate diphosphokinase activity;protein binding;ATP binding;kinase activity;identical protein binding;protein homodimerization activity