HPD

4-hydroxyphenylpyruvate dioxygenase, the group of Glyoxalase domain containing family

Basic information

Region (hg38): 12:121839527-121863596

Previous symbols: [ "PPD" ]

Links

ENSG00000158104 ∙ NCBI:3242 ∙ OMIM:609695 ∙ HGNC:5147 ∙ Uniprot:P32754 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hawkinsinuria (Strong), mode of inheritance: AD
• tyrosinemia type III (Strong), mode of inheritance: AR
• tyrosinemia type III (Supportive), mode of inheritance: AR
• hawkinsinuria (Limited), mode of inheritance: Unknown
• hawkinsinuria (Limited), mode of inheritance: AD
• tyrosinemia type III (Definitive), mode of inheritance: AR
• tyrosinemia type III (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hawksinuria; Tyrosinemia, type III	AD/AR	Biochemical	In Tyrosinemia III, specific dietary measures (eg, restriction of phenylalanine and tyrosine) are recommended; In Hawksinuria, individuals may present with manifestations including failure to thrive, and a protein-restricted diet has been reported as beneficial in some instances	Biochemical; Neurologic	1130176; 858207; 7278885; 6828337; 6132360; 1519651; 9343288; 10412819; 10942115; 11073718; 11916315; 17560158
It is unclear if a strict low tyrosine diet alters the natural history of tyrosinemia type III, though some have suggested that treatment may be important, especially in infancy

ClinVar

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

• Tyrosinemia type III;Hawkinsinuria (10 variants)
• Hawkinsinuria;Tyrosinemia type III (6 variants)
• Tyrosinemia type III (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HPD 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				95	3	98
missense			58	1	5	64
nonsense	3	2	2			7
start loss						0
frameshift	14	3	1			18
inframe indel			1			1
splice donor/acceptor (+/-2bp)		5	1		1	7
splice region			7	28	1	36
non coding			6	96	18	120
Total	17	10	69	192	27

Highest pathogenic variant AF is 0.0000132

Variants in HPD

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

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

Position	Type	Phenotype	Significance	ClinVar
12-121839537-G-A		Hawkinsinuria • Tyrosinemia type III	Uncertain significance (Jan 13, 2018)
12-121839538-C-A		Tyrosinemia type III • Hawkinsinuria	Uncertain significance (Jan 13, 2018)
12-121839646-A-G		Hawkinsinuria • Tyrosinemia type III	Uncertain significance (Jan 12, 2018)
12-121839659-G-A		Hawkinsinuria • Tyrosinemia type III	Uncertain significance (Jan 13, 2018)
12-121839663-T-C		Tyrosinemia type III • Hawkinsinuria	Uncertain significance (Jan 13, 2018)
12-121839734-G-A		Hawkinsinuria;Tyrosinemia type III	Likely benign (Sep 15, 2023)
12-121839737-G-C		Hawkinsinuria;Tyrosinemia type III	Likely benign (Jan 09, 2024)
12-121839745-C-G		Tyrosinemia type III • Hawkinsinuria	Uncertain significance (Jan 13, 2018)
12-121839746-C-T		Hawkinsinuria;Tyrosinemia type III	Likely benign (Apr 07, 2023)
12-121839751-T-C		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Dec 03, 2021)
12-121839755-C-T		Hawkinsinuria;Tyrosinemia type III	Likely benign (Apr 18, 2023)
12-121839758-CA-C		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Aug 21, 2017)
12-121839776-C-T		Hawkinsinuria;Tyrosinemia type III	Likely benign (Jan 24, 2024)
12-121839777-C-G		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Apr 24, 2021)
12-121839788-C-T			Likely benign (Mar 01, 2023)
12-121839789-T-A		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Jun 22, 2022)
12-121839790-C-T		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Aug 13, 2021)
12-121839794-C-T		Hawkinsinuria;Tyrosinemia type III	Likely benign (Aug 09, 2022)
12-121839802-C-T		Tyrosinemia type III • Hawkinsinuria	Conflicting classifications of pathogenicity (Jan 12, 2018)
12-121839804-T-C		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Oct 03, 2022)
12-121839806-G-T		Inborn genetic diseases	Uncertain significance (Jan 25, 2023)
12-121839812-T-C		Hawkinsinuria;Tyrosinemia type III	Likely benign (Nov 30, 2023)
12-121839813-G-T		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Dec 21, 2020)
12-121839818-G-T		Hawkinsinuria;Tyrosinemia type III	Uncertain significance (Aug 19, 2022)
12-121839824-G-T		Hawkinsinuria;Tyrosinemia type III	Likely benign (Nov 20, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HPD	protein_coding	protein_coding	ENST00000289004	14	24070

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000528	0.998	125711	0	36	125747	0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.730	194	225	0.863	0.0000142	2593
Missense in Polyphen		63	79.945	0.78804		897
Synonymous	-0.729	105	95.9	1.09	0.00000674	734
Loss of Function	2.84	10	25.5	0.393	0.00000129	297

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000119	0.000119
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000123	0.000123
Middle Eastern	0.0000544	0.0000544
South Asian	0.000490	0.000490
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key enzyme in the degradation of tyrosine.
• Disease: DISEASE: Tyrosinemia 3 (TYRSN3) [MIM:276710]: An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation. {ECO:0000269|PubMed:10942115, ECO:0000269|PubMed:11073718}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hawkinsinuria (HAWK) [MIM:140350]: An inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine. {ECO:0000269|PubMed:11073718}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquinone and other terpenoid-quinone biosynthesis - Homo sapiens (human);Phenylalanine metabolism - Homo sapiens (human);Tyrosine metabolism - Homo sapiens (human);Tyrosinemia, transient, of the newborn;Dopamine beta-hydroxylase deficiency;Disulfiram Action Pathway;Phenylalanine and Tyrosine Metabolism;Tyrosine Metabolism;Alkaptonuria;Monoamine oxidase-a deficiency (MAO-A);Hawkinsinuria;Tyrosinemia Type I;Phenylketonuria;Tyrosinemia Type 3 (TYRO3);Tyrosinemia Type 2 (or Richner-Hanhart syndrome);Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism;Metabolism of amino acids and derivatives;Tyrosine metabolism;Phenylalanine and tyrosine catabolism;Metabolism;tyrosine degradation;Tyrosine metabolism (Consensus)

Recessive Scores

• pRec: 0.355

Intolerance Scores

• loftool: 0.747
• rvis_EVS: 0.46
• rvis_percentile_EVS: 78.69

Haploinsufficiency Scores

• pHI: 0.0953
• hipred: N
• hipred_score: 0.476
• ghis: 0.398

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hpd
• Phenotype: homeostasis/metabolism phenotype; renal/urinary system phenotype

Gene ontology

• Biological process: L-phenylalanine catabolic process;tyrosine catabolic process;oxidation-reduction process
• Cellular component: Golgi membrane;endoplasmic reticulum membrane;cytosol;extracellular exosome
• Molecular function: 4-hydroxyphenylpyruvate dioxygenase activity;metal ion binding