HAAO

3-hydroxyanthranilate 3,4-dioxygenase

Basic information

Region (hg38): 2:42767088-42792593

Links

ENSG00000162882 ∙ NCBI:23498 ∙ OMIM:604521 ∙ HGNC:4796 ∙ Uniprot:P46952 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• vertebral, cardiac, renal, and limb defects syndrome 1 (Strong), mode of inheritance: AR
• vertebral, cardiac, renal, and limb defects syndrome 1 (Limited), mode of inheritance: AR
• congenital vertebral-cardiac-renal anomalies syndrome (Supportive), mode of inheritance: AR
• vertebral, cardiac, renal, and limb defects syndrome 1 (Strong), mode of inheritance: AR
• vertebral, cardiac, renal, and limb defects syndrome 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Vertebral, cardiac, renal, and limb defects syndrome 1	AR	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early identifcation and management	Cardiovascular; Gastrointestinal; Musculoskeletal; Renal	28792876
The condition can involve multiple congenital anomalies

ClinVar

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

• Vertebral, cardiac, renal, and limb defects syndrome 1 (14 variants)
• Inborn genetic diseases (12 variants)
• not provided (5 variants)
• Congenital NAD deficiency disorder (5 variants)
• HAAO-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HAAO 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			1
missense		2	15	1	2	20
nonsense	1					1
start loss						0
frameshift	1	1				2
inframe indel						0
splice donor/acceptor (+/-2bp)		1				1
splice region						0
non coding					3	3
Total	2	4	16	1	5

Highest pathogenic variant AF is 0.0000197

Variants in HAAO

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

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

Position	Type	Phenotype	Significance	ClinVar
2-42767441-C-A		not specified	Uncertain significance (Aug 02, 2021)
2-42767507-C-G		not specified	Uncertain significance (Feb 14, 2024)
2-42767631-G-A		not specified	Uncertain significance (Jan 29, 2024)
2-42767637-C-G		not specified	Uncertain significance (Aug 21, 2023)
2-42767674-C-G		HAAO-related disorder	Benign (Jun 08, 2019)
2-42767878-G-A			Uncertain significance (Mar 08, 2022)
2-42767901-C-T		HAAO-related disorder	Uncertain significance (Aug 29, 2023)
2-42767918-T-C		HAAO-related disorder	Benign (Jun 17, 2019)
2-42769679-G-A		Vertebral, cardiac, renal, and limb defects syndrome 1	Benign (Aug 10, 2021)
2-42769767-C-T		HAAO-related disorder	Likely benign (Feb 08, 2024)
2-42769777-C-T		not specified	Uncertain significance (Dec 21, 2022)
2-42769785-C-T		Congenital NAD deficiency disorder • Vertebral, cardiac, renal, and limb defects syndrome 1	Pathogenic (Apr 16, 2018)
2-42769819-C-G		Vertebral, cardiac, renal, and limb defects syndrome 1	Uncertain significance (Jul 25, 2022)
2-42769819-C-T		not specified	Uncertain significance (Jun 02, 2023)
2-42770143-C-CA		Vertebral, cardiac, renal, and limb defects syndrome 1 • Congenital NAD deficiency disorder	Pathogenic (Apr 16, 2018)
2-42770474-G-A		Vertebral, cardiac, renal, and limb defects syndrome 1	Benign (Aug 10, 2021)
2-42770502-A-G		Vertebral, cardiac, renal, and limb defects syndrome 1	Uncertain significance (Jul 25, 2022)
2-42770521-C-T		not specified	Uncertain significance (Jul 19, 2023)
2-42770527-C-T		not specified	Uncertain significance (May 17, 2023)
2-42770550-A-G			Uncertain significance (Nov 28, 2022)
2-42783341-C-T		Congenital NAD deficiency disorder • Vertebral, cardiac, renal, and limb defects syndrome 1	Likely pathogenic (Nov 24, 2021)
2-42783363-C-A		Congenital NAD deficiency disorder • Vertebral, cardiac, renal, and limb defects syndrome 1	Likely pathogenic (Nov 24, 2021)
2-42783366-C-T		not specified	Likely benign (Dec 01, 2022)
2-42783375-C-T		not specified	Uncertain significance (Oct 10, 2023)
2-42783413-A-G		Vertebral, cardiac, renal, and limb defects syndrome 1	Likely pathogenic (Mar 29, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HAAO	protein_coding	protein_coding	ENST00000294973	10	25505

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.06e-8	0.537	125703	0	45	125748	0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.177	167	161	1.04	0.00000875	1814
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000313	0.000304
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000691	0.0000544
Finnish	0.0000470	0.0000462
European (Non-Finnish)	0.000220	0.000211
Middle Eastern	0.0000691	0.0000544
South Asian	0.000377	0.000359
Other	0.00	0.00

dbNSFP

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.
• Pathway: Tryptophan metabolism - Homo sapiens (human);Tyrosinemia, transient, of the newborn;Dopamine beta-hydroxylase deficiency;Disulfiram Action Pathway;Tyrosine Metabolism;Alkaptonuria;Monoamine oxidase-a deficiency (MAO-A);Hawkinsinuria;Tyrosinemia Type I;Tryptophan Metabolism;NAD Biosynthesis II (from tryptophan);Tryptophan metabolism;Tryptophan catabolism;Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism;Metabolism of amino acids and derivatives;tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde;Metabolism;L-kynurenine degradation;NAD <i>de novo</i> biosynthesis;Tryptophan degradation;superpathway of tryptophan utilization;tryptophan degradation (Consensus)

Recessive Scores

• pRec: 0.0947

Intolerance Scores

• loftool: 0.828
• rvis_EVS: 0.53
• rvis_percentile_EVS: 80.82

Haploinsufficiency Scores

• pHI: 0.222
• hipred: N
• hipred_score: 0.216
• ghis: 0.409

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.859

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Haao
• Phenotype: homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: tryptophan catabolic process;NAD biosynthetic process;response to zinc ion;quinolinate biosynthetic process;electron transport chain;'de novo' NAD biosynthetic process from tryptophan;anthranilate metabolic process;response to cadmium ion;quinolinate metabolic process;neuron cellular homeostasis
• Cellular component: cytoplasm;cytosol
• Molecular function: 3-hydroxyanthranilate 3,4-dioxygenase activity;protein binding;ferrous iron binding;electron transfer activity