HAAO

protein-coding

3-hydroxyanthranilate 3,4-dioxygenase

Gene summary

3-Hydroxyanthranilate 3,4-dioxygenase is a monomeric cytosolic protein belonging to the family of intramolecular dioxygenases containing nonheme ferrous iron. It is widely distributed in peripheral organs, such as liver and kidney, and is also present in low amounts in the central nervous system. HAAO catalyzes the synthesis of quinolinic acid (QUIN) from 3-hydroxyanthranilic acid. QUIN is an excitotoxin whose toxicity is mediated by its ability to activate glutamate N-methyl-D-aspartate receptors. Increased cerebral levels of QUIN may participate in the pathogenesis of neurologic and inflammatory disorders. HAAO has been suggested to play a role in disorders associated with altered tissue levels of QUIN. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012205.3

Inheritance

ClinVar variants

P:14U:52B:16

Top phenotype

Vertebral, cardiac, renal, and limb defects syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr2:42,767,089-42,792,593

External References & Databases

Ensembl (ENSG00000162882)

Transcript & Mutation Effects

hg38 • Region Span ~25.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vertebral, cardiac, renal, and limb defects syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060554

Submitter: ClinGen

*HAAO* was first reported in relation to autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 1 in 2017 (Shi H, et al., 2017, PMID: 28792876). Seven unique variants (missense, nonsense, and frameshift) have been reported in 5 probands in 2 publications (PMIDs: 28792876, 33942433). In addition to this case-level data experimental evidence includes its biochemical function in the kynurenine pathway (PMID: 7514594) and a knockout mouse model (PMID: 28792876). In summary, *HAAO* is definitively associated with vertebral, cardiac, renal, and limb defects syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Aminoacidopathy GCEP on 07/10/2020. It was reevaluated on 06/24/2022. As a result of this reevaluation, the classification changed from Limited to Definitive due to a new case reports (PMID: 33942433).

vertebral, cardiac, renal, and limb defects syndrome 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060554

Submitter: Ambry Genetics

vertebral, cardiac, renal, and limb defects syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060554

Submitter: PanelApp Australia

vertebral, cardiac, renal, and limb defects syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060554

Submitter: Labcorp Genetics (formerly Invitae)

congenital vertebral-cardiac-renal anomalies syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020831

Submitter: Orphanet

vertebral, cardiac, renal, and limb defects syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060554

Submitter: G2P

Clinical Genomic Database (CGD)

Vertebral, cardiac, renal, and limb defects syndrome 1AR

Manifestation: Cardiovascular; Gastrointestinal; Musculoskeletal; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early identifcation and management

Comments: The condition can involve multiple congenital anomalies

Refs: 28792876

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HAAO variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 62

Vertebral, cardiac, renal, and limb defects syndrome 1Total: 16

HAAO-related disorderTotal: 9

not providedTotal: 8

Congenital NAD deficiency disorderTotal: 7

Monogenic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012205.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	7 clinvar	2 clinvar	10
missense	1 clinvar	4 clinvar	49 clinvar	7 clinvar		61
nonsense	1 clinvar					1
start loss						0
frameshift	2 clinvar	3 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)		3 clinvar	1 clinvar			4
Total	4	10	52	14	2	82

Highest pathogenic variant AF is 0.000025753847

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012205.3	RefSeq	NP_036337.2	10	MANE Select
ENST00000294973.11	Ensembl	ENSP00000294973.6	10	MANE Select
ENST00000431905.1	Ensembl	ENSP00000412601.1	6	Standard
ENST00000878437.1	Ensembl	ENSP00000548496.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

tryptophan catabolic process
NAD biosynthetic process
response to zinc ion
quinolinate biosynthetic process
electron transport chain

Molecular Function

3-hydroxyanthranilate 3,4-dioxygenase activity
protein binding
ferrous iron binding
electron transfer activity

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000294973
Coding exons: 10
Length: 25505
Individuals with no LoFs: 125703
Homozygous LoFs: 0
Heterozygous LoFs: 45
Defined: 125748
p: 0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.177	167	161	1.04	0.00000875	1814
Missense (PolyPhen)		53	51.619	1.0267		600
Synonymous	-0.830	73	64.5	1.13	0.00000348	554
Loss of Function	1.08	15	20.2	0.741	0.00000123	191

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000069	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00022	0.00021	rare
South Asian	0.00038	0.00036	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the oxidative ring opening of 3- hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinate. {ECO:0000255|HAMAP- Rule:MF_03019, ECO:0000269|PubMed:28792876, ECO:0000269|PubMed:7514594}.;
Disease: DISEASE: Vertebral, cardiac, renal, and limb defects syndrome 1 (VCRL1) [MIM:617660]: An autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal defects, and distal mild limb defects. {ECO:0000269|PubMed:28792876}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0947

Intolerance Scores

LoFtool: 0.828
RVIS EVS: 0.53
RVIS percentile EVS: 80.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.859

Gene Damage Prediction

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