HNMT

protein-coding

histamine N-methyltransferase, the group of 7BS small molecule methyltransferases

Gene summary

In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006895.3

Inheritance

ClinVar variants

P:4U:37B:16

Top phenotype

Intellectual development disorder, autosomal recessive 51

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr2:137,964,020-138,016,364

External References & Databases

Ensembl (ENSG00000150540)

Transcript & Mutation Effects

hg38 • Region Span ~52.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 51LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014759

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 51STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014759

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 51STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014759

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual development disorder, autosomal recessive 51AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26206890

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNMT variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 35

not providedTotal: 18

Intellectual disability, autosomal recessive 51Total: 8

HNMT-related disorderTotal: 4

Inherited susceptibility to asthmaTotal: 2

Pulmonary arterial hypertensionTotal: 1

Paediatric disordersTotal: 1

HNMT-Related DisordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006895.3. 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	12 clinvar	1 clinvar	14
missense	1 clinvar	2 clinvar	32 clinvar	3 clinvar		38
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	3	37	15	1	57

Highest pathogenic variant AF is 0.00000895032

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006895.3	RefSeq	NP_008826.1	6	MANE Select
ENST00000280097.5	Ensembl	ENSP00000280097.3	6	MANE Select
NM_001024074.3	RefSeq	NP_001019245.1	2	Standard
NM_001024075.3	RefSeq	NP_001019246.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Histidine metabolism - Homo sapiens (human)
Histidine Metabolism
Histidinemia
Amino Acid metabolism
Metapathway biotransformation Phase I and II

Biological Process

histamine catabolic process
histidine catabolic process
brain development
respiratory gaseous exchange
methylation

Molecular Function

histamine N-methyltransferase activity

Cellular Component

cytoplasm
cytosol
neuron projection
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000280097
Coding exons: 6
Length: 52341
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125735
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.661	127	150	0.848	0.00000694	1957
Missense (PolyPhen)		41	40.362	1.0158		568
Synonymous	0.377	50	53.5	0.934	0.00000266	509
Loss of Function	2.09	5	13.2	0.379	5.57e-7	176

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00034	0.00033	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine. {ECO:0000269|PubMed:26206890}.;
Disease: DISEASE: Mental retardation, autosomal recessive 51 (MRT51) [MIM:616739]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:26206890}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.;

Recessive Scores

pRec: 0.238

Intolerance Scores

LoFtool: 0.483
RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.884

Gene Damage Prediction

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