PTS

6-pyruvoyltetrahydropterin synthase

Basic information

Region (hg38): 11:112226366-112269955

Links

ENSG00000150787 ∙ NCBI:5805 ∙ OMIM:612719 ∙ HGNC:9689 ∙ Uniprot:Q03393 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• BH4-deficient hyperphenylalaninemia A (Definitive), mode of inheritance: AR
• BH4-deficient hyperphenylalaninemia A (Strong), mode of inheritance: AR
• BH4-deficient hyperphenylalaninemia A (Supportive), mode of inheritance: AR
• BH4-deficient hyperphenylalaninemia A (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperphenylalaninemia, BH4-deficient, A	AR	Biochemical	Dietary measures and/or medical treatment (eg, L-dopa, tetrahydrobiopterin) can be beneficial	Biochemical; Neurologic	7094929; 6142058; 3297709; 3308682; 8178819; 9222757; 9222755; 2027491; 11438997; 11916314; 1388593; 16364672; 20059486

ClinVar

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

• 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (227 variants)
• not provided (41 variants)
• Inborn genetic diseases (11 variants)
• not specified (3 variants)
• Hyperphenylalaninemia, bh4-deficient, a, due to partial pts deficiency (2 variants)
• PTS-related condition (2 variants)
• Seizure (1 variants)
• Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PTS 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				43	1	44
missense	10	19	28	1		58
nonsense	6	3				9
start loss	2	2				4
frameshift	4	6				10
inframe indel		1				1
splice donor/acceptor (+/-2bp)	3	14				17
splice region	1	1	4	25	3	34
non coding	1		11	33	9	54
Total	26	45	39	77	10

Highest pathogenic variant AF is 0.0000132

Variants in PTS

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

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

Position	Type	Phenotype	Significance	ClinVar
11-112226417-CCGAGCACCGCAGACAGCGCCGGGAAGATGAGCA-C		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Pathogenic/Likely pathogenic (Oct 13, 2023)
11-112226444-A-G		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Pathogenic (Sep 20, 2023)
11-112226445-T-G		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely pathogenic (-)
11-112226446-G-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Pathogenic (Dec 18, 2023)
11-112226452-G-A		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Sep 17, 2021)
11-112226454-A-G		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Uncertain significance (Mar 09, 2022)
11-112226460-G-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Uncertain significance (Dec 18, 2023)
11-112226464-C-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Jun 05, 2019)
11-112226465-C-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Uncertain significance (Aug 30, 2021)
11-112226464-C-CCGTCG		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely pathogenic (Jan 29, 2022)
11-112226467-T-C		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Feb 27, 2022)
11-112226468-C-T		not specified	Uncertain significance (Aug 05, 2021)
11-112226469-G-A		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Conflicting classifications of pathogenicity (Jan 12, 2022)
11-112226479-A-G		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Aug 26, 2021)
11-112226483-G-A		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
11-112226487-C-T			Likely pathogenic (Feb 17, 2016)
11-112226488-C-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Jun 11, 2023)
11-112226489-C-T		Hyperphenylalaninemia, bh4-deficient, a, due to partial pts deficiency • 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Conflicting classifications of pathogenicity (Apr 22, 2023)
11-112226490-G-A		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Uncertain significance (Aug 10, 2022)
11-112226491-C-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (May 09, 2022)
11-112226497-C-A		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Jul 11, 2022)
11-112226500-C-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Aug 06, 2022)
11-112226506-C-T		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Nov 20, 2023)
11-112226508-C-G		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely pathogenic (Dec 30, 2020)
11-112226509-G-A		6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Likely benign (Nov 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PTS	protein_coding	protein_coding	ENST00000280362	6	43591

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000646	0.285	125724	0	22	125746	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.126	76	79.1	0.960	0.00000379	963
Missense in Polyphen		24	23.689	1.0131		293
Synonymous	-0.930	36	29.6	1.22	0.00000161	257
Loss of Function	0.0737	8	8.23	0.972	3.54e-7	102

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	0.0000463	0.0000462
European (Non-Finnish)	0.000152	0.000149
Middle Eastern	0.00	0.00
South Asian	0.000100	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6- pyruvoyl tetrahydropterin. {ECO:0000269|PubMed:1282802}.
• Disease: DISEASE: Hyperphenylalaninemia, BH4-deficient, A (HPABH4A) [MIM:261640]: An autosomal recessive disorder characterized by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits. Neurological symptoms are unresponsive to the classic phenylalanine-low diet. {ECO:0000269|PubMed:10220141, ECO:0000269|PubMed:10531334, ECO:0000269|PubMed:10585341, ECO:0000269|PubMed:10874306, ECO:0000269|PubMed:11388593, ECO:0000269|PubMed:7493990, ECO:0000269|PubMed:7698774, ECO:0000269|PubMed:8178819, ECO:0000269|PubMed:8707300, ECO:0000269|PubMed:9159737, ECO:0000269|PubMed:9222757, ECO:0000269|PubMed:9450907}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Folate biosynthesis - Homo sapiens (human);Sepiapterin reductase deficiency;Segawa syndrome;Pterine Biosynthesis;Dopa-responsive dystonia;Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiency;Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps);Hyperphenylalaninemia due to dhpr-deficiency;tetrahydrobiopterin <i>de novo</i> biosynthesis;Folate metabolism;Biopterin metabolism;Metabolism;Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation;Metabolism of cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.617

Intolerance Scores

• loftool: 0.442
• rvis_EVS: -0.12
• rvis_percentile_EVS: 44.54

Haploinsufficiency Scores

• pHI: 0.113
• hipred: Y
• hipred_score: 0.688
• ghis: 0.610

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.987

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pts
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland 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); growth/size/body region phenotype; reproductive system 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); 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); digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); pigmentation phenotype

Gene ontology

• Biological process: cellular amino acid metabolic process;tetrahydrobiopterin biosynthetic process;central nervous system development;cofactor metabolic process
• Cellular component: cytoplasm;mitochondrion;cytosol
• Molecular function: 6-pyruvoyltetrahydropterin synthase activity;protein binding;identical protein binding;protein homodimerization activity;metal ion binding