HGD

protein-coding

homogentisate 1,2-dioxygenase

Gene summary

This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.[provided by RefSeq, May 2010]

Previous symbols:

MANE transcript

NM_000187.4

Inheritance

ClinVar variants

P:270U:121B:119

Top phenotype

Alkaptonuria

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr3:120,628,172-120,682,269

External References & Databases

Ensembl (ENSG00000113924)

Transcript & Mutation Effects

hg38 • Region Span ~54.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

alkaptonuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008753

Submitter: ClinGen

HGD was first reported in relation to autosomal recessive inheritance of alkaptonuria in 1996 (Fernández-Cañón JM, et al., 1996, PMID: 8782815). At least 115 unique variants (including many missense and nonsense, several splicing, and some frameshift, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 8782815, 9529363, 9154114, 9674916). Variants in this gene segregated with disease in 18 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by the biochemical function of HGD, its expression in the liver, and a mouse model which displays high levels of urinary homogentisic acid, as observed in humans (PMIDs: 13271328, 8782815, 8188247). HGD functions in phenylalanine and tyrosine metabolism to convert homogentisate to maleylacetoacetate; in the absence of HGD activity accumulation of homogentisate results in alkaptonuria. In summary, HGD is definitively associated with autosomal recessive inheritance of alkaptonuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

alkaptonuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008753

Submitter: Orphanet

alkaptonuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008753

Submitter: Labcorp Genetics (formerly Invitae)

alkaptonuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008753

Submitter: Natera

alkaptonuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008753

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

AlkaptonuriaAR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Renal

Intervention: Biochemical; Cardiovascular; Musculoskeletal; Renal

Rationale: The condition can include cardiac complications, and surveillance for early detection and management of manifestations such as aortic dilatation, valvular disease, or coronary artery calcification may be beneficial; Awareness of complications including urolithiasis and joint degeneration may allow prompt recognition and treatment; Other, more specific therapies are under investigation

Refs: 12784973; 5472968; 2667832; 2771520; 2270175; 2316305; 8782815; 9154114; 9529363; 9809834; 10482952; 10594001; 11001939; 10970188; 10945668; 12359141; 12501223; 12872815; 15260431; 20301627; 21620748; 21927854; 22482092; 22772574; 23035044; 23357094; 23353776; 23430897; 23430917; 23438536; 23466771; 23486607; 23619548; 23879342; 24009934; 24009959

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HGD variants in ClinVar

7 Conditions Cataloged

AlkaptonuriaTotal: 587

Inborn genetic diseasesTotal: 44

not providedTotal: 29

not specifiedTotal: 22

HGD-related disorderTotal: 16

HGD-related disordersTotal: 7

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000187.4. 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	3 clinvar	2 clinvar	3 clinvar	109 clinvar		117
missense	73 clinvar	55 clinvar	116 clinvar	10 clinvar		254
nonsense	19 clinvar	16 clinvar	1 clinvar			36
start loss	3 clinvar					3
frameshift	43 clinvar	19 clinvar				62
splice donor/acceptor (+/-2bp)	21 clinvar	16 clinvar	1 clinvar			38
Total	162	108	121	119	0	510

Highest pathogenic variant AF is 0.00020940125

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 83 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000187.4	RefSeq	NP_000178.2	14	MANE Select
ENST00000283871.10	Ensembl	ENSP00000283871.5	14	MANE Select
ENST00000475447.2	Ensembl	ENSP00000417977.2	4	Standard
ENST00000476082.2	Ensembl	ENSP00000419560.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tyrosine metabolism - Homo sapiens (human)
Tyrosinemia, transient, of the newborn
Dopamine beta-hydroxylase deficiency
Disulfiram Action Pathway
Phenylalanine and Tyrosine Metabolism

Biological Process

cellular amino acid metabolic process
L-phenylalanine catabolic process
tyrosine catabolic process
oxidation-reduction process

Molecular Function

homogentisate 1,2-dioxygenase activity
protein binding
identical protein binding
metal ion binding

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000283871
Coding exons: 14
Length: 54399
Individuals with no LoFs: 125664
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125746
p: 0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.290	223	236	0.947	0.0000125	2948
Missense (PolyPhen)		99	100.66	0.98353		1220
Synonymous	-1.86	106	84.3	1.26	0.00000463	820
Loss of Function	1.81	16	26.0	0.616	0.00000129	316

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00091	0.00091	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.235

Intolerance Scores

LoFtool: 0.273
RVIS EVS: -0.38
RVIS percentile EVS: 28.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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