HAL

protein-coding

histidine ammonia-lyase

Gene summary

Histidine ammonia-lyase is a cytosolic enzyme catalyzing the first reaction in histidine catabolism, the nonoxidative deamination of L-histidine to trans-urocanic acid. Histidine ammonia-lyase defects cause histidinemia which is characterized by increased histidine and histamine and decreased urocanic acid in body fluids. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

Previous symbols:

MANE transcript

NM_002108.4

Inheritance

AR, AD

ClinVar variants

P:1U:135B:14

Top phenotype

Histidinemia

gnomAD constraint

pLI —, LoF o/e 0.98

Max pathogenic AF

—

Genomic locus

chr12:95,972,662-95,996,365

External References & Databases

Ensembl (ENSG00000084110)

Transcript & Mutation Effects

hg38 • Region Span ~23.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

histidinemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009345

Submitter: PanelApp Australia

histidinemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009345

Submitter: ClinGen

*HAL* was first reported in relation to autosomal recessive histidinemia in 2005 (Kawai Y, et al., 2005, PMID: 15806399). The disease was first described by Ghadimi et al in 1961, who observed elevated levels of histidine in blood and urine of two patients. This metabolic disorder seems to be benign in most affected individuals, although, under unusual circumstances, the disorder may be harmful and produce the central nervous system disease noted in a few histidinemic patients (Reviewed in Levy H., Histidinemia. Orphanet encyclopedia, May 2002). HAL catalyzes the reaction: L-histidine = urocanate + NH3; in patients with deficiency of HAL there is a consequent accumulation of histidine and decreased concentration of urocanate. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Biallelic missense variants in this gene have been reported in at least 1 proband in 1 publication (PMID: 15806399). At least 7 additional variants (splice site, nonsense, missense, and frameshift) have been associated with mildly increased histidine levels in the heterozygous state (PMIDs: 25575548, 27453504, 26990548). This gene-disease relationship is supported by the biochemical function of HAL which is consistent with the biochemical abnormalities observed in individuals with histidinemia (Takeuchi, J. Biochem., Japan, 34, 1 (1941)), the functional alteration in patient cells (PMID: 7211776) and the biochemical features of a histidinemic mouse (PMID: 8486363). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 09/25/2020. It was reevaluated on 10/24/2023. As a result of this reevaluation, the classification remained Limited with no new evidence identified.

histidinemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009345

Submitter: Orphanet

histidinemiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009345

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

HistidinemiaAR

Manifestation: Biochemical

Intervention: General

Rationale: The clinical relevance of the condition is unclear

Comments: The clinical relevance of the condition is unclear

Refs: 13704885; 13863215; 4421298; 6192285; 6410118; 8669938; 15806399; 20156889

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HAL variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 92

HistidinemiaTotal: 59

not providedTotal: 12

HAL-related disorderTotal: 9

Increased histidineTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002108.4. 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			8 clinvar	10 clinvar		18
missense			120 clinvar	3 clinvar	1 clinvar	124
nonsense			3 clinvar			3
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	0	1	135	13	1	150

Highest pathogenic variant AF is 0.000002736738

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002108.4	RefSeq	NP_002099.1	20	MANE Select
ENST00000261208.8	Ensembl	ENSP00000261208.3	20	MANE Select
NM_001258333.2	RefSeq	NP_001245262.1	13	Standard
NM_001258334.2	RefSeq	NP_001245263.1	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hal	Danio rerio	Structure: hematopoietic stem cell differentiation Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

hal

Danio rerio

Structure: hematopoietic stem cell differentiation

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Histidine metabolism - Homo sapiens (human)
Histidine Metabolism
Ammonia Recycling
Histidinemia
Amino Acid metabolism

Biological Process

histidine catabolic process
histidine catabolic process to glutamate and formamide
histidine catabolic process to glutamate and formate

Molecular Function

histidine ammonia-lyase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261208
Coding exons: 20
Length: 23704
Individuals with no LoFs: 125345
Homozygous LoFs: 1
Heterozygous LoFs: 402
Defined: 125748
p: 0.00160

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.259	388	374	1.04	0.0000234	4248
Missense (PolyPhen)		156	150.59	1.0359		1699
Synonymous	-0.892	153	140	1.10	0.00000889	1324
Loss of Function	0.0848	35	35.5	0.985	0.00000181	428

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0091	0.0091	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.0015	0.0015	notable
South Asian	0.00069	0.00069	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Histidinemia (HISTID) [MIM:235800]: Autosomal recessive disease characterized by increased histidine and histamine as well as decreased urocanic acid in body fluids. {ECO:0000269|PubMed:15806399}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.672
RVIS EVS: -0.66
RVIS percentile EVS: 16.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.730

Gene Damage Prediction

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