HINT1

protein-coding

histidine triad nucleotide binding protein 1, the group of Histidine triad superfamily

Gene summary

This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed. [provided by RefSeq, Dec 2015]

Previous symbols:

PRKCNH1
HINT

MANE transcript

NM_005340.7

Inheritance

ClinVar variants

P:30U:52B:18

Top phenotype

Neuromyotonia and axonal neuropathy, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr5:131,155,383-131,224,468

External References & Databases

Ensembl (ENSG00000169567)

Transcript & Mutation Effects

hg38 • Region Span ~69.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Gamstorp-Wohlfart syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007646

Submitter: G2P

Charcot-Marie-Tooth diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: ClinGen

HINT1 was first reported in relation to autosomal recessive Charcot-Marie-Tooth disease in 2012, characterized as an axonal neuropathy with neuromyotonia (Zimon et al., PMID: 22961002). Although neuromyotonia was initially defined as a core feature of the disorder, reports of probands without neuromyotonia indicated incomplete penetrance for this phenotype. At least twelve unique variants (e.g. missense, nonsense, frameshift, etc.) have been reported in humans, with the most common pathogenic variant c.110G>C (p.Arg37Pro) being a founder variant observed mainly in patients of Slavic origin (PMID: 31848916). 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 ten probands in five publications (PMIDs: 26059562, 24105373, 25342199, 30001929, 22961002) and segregated with disease in four additional family members. These probands generally present with a primary axonal neuropathy characterized by gait impairment, progressive distal muscle weakness and atrophy, facial/foot deformities, and neuromyotonia. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, as the mutant proteins are unable to fulfill HINT1's signalling role in the central and peripheral nervous system (PMID: 33404983). This gene-disease association is supported by expression evidence, HINT1's biochemical function in the nervous system, and a series of functional studies performed on pathogenic variants in cell and animal models. Primary expression in the CNS and PNS indicates the crucial role that the protein fulfills, while loss of the sumolayse activity that HINT1 provides matches with the primary motor neuropathy phenotypes observed in probands (PMID: 31088288). Additionally, functional evaluation of all known pathogenic variants demonstrated a variety of altered functions including impaired thermal stability, disrupted dimer formation, and loss of interaction with SUMO1, CaM, and ICD Teneurin 1 (PMID: 33404983). In summary, HINT1 is definitively associated with autosomal recessive Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Gamstorp-Wohlfart syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007646

Submitter: Labcorp Genetics (formerly Invitae)

Gamstorp-Wohlfart syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007646

Submitter: Orphanet

Gamstorp-Wohlfart syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007646

Submitter: PanelApp Australia

Gamstorp-Wohlfart syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007646

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neuromyotonia and axonal neuropathy, autosomal recessiveAR

Manifestation: Musculoskeletal

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: 22961002

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HINT1 variants in ClinVar

9 Conditions Cataloged

Autosomal recessive axonal neuropathy with neuromyotoniaTotal: 90

not providedTotal: 26

Inborn genetic diseasesTotal: 26

not specifiedTotal: 7

Charcot-Marie-Tooth diseaseTotal: 4

HINT1-related disorderTotal: 3

HINT1-related disordersTotal: 3

Peripheral neuropathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005340.7. 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				16 clinvar	1 clinvar	17
missense	3 clinvar	12 clinvar	50 clinvar	1 clinvar		66
nonsense	5 clinvar		1 clinvar			6
start loss	1 clinvar					1
frameshift	6 clinvar		1 clinvar			7
splice donor/acceptor (+/-2bp)		3 clinvar				3
Total	15	15	52	17	1	100

Highest pathogenic variant AF is 0.00022185233

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005340.7	RefSeq	NP_005331.1	3	MANE Select
ENST00000304043.10	Ensembl	ENSP00000304229.5	3	MANE Select
NM_001437949.1	RefSeq	NP_001424878.1	3	Standard
NM_001437950.1	RefSeq	NP_001424879.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
signal transduction
purine ribonucleotide catabolic process
positive regulation of calcium-mediated signaling
intrinsic apoptotic signaling pathway by p53 class mediator

Molecular Function

nucleotide binding
protein kinase C binding
hydrolase activity

Cellular Component

histone deacetylase complex
nucleus
cytosol
cytoskeleton
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304043
Coding exons: 3
Length: 12709
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.442	63	73.7	0.855	0.00000349	828
Missense (PolyPhen)		17	19.331	0.87941		245
Synonymous	0.646	20	24.0	0.832	0.00000113	246
Loss of Function	0.0864	4	4.19	0.954	2.41e-7	51

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hydrolyzes purine nucleotide phosphoramidates with a single phosphate group, including adenosine 5'monophosphoramidate (AMP-NH2), adenosine 5'monophosphomorpholidate (AMP-morpholidate) and guanosine 5'monophosphomorpholidate (GMP-morpholidate). Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase, as well as Met-AMP, His- AMP and Asp-AMP, lysyl-GMP (GMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) and AMP-N-alanine methyl ester. Can also convert adenosine 5'-O-phosphorothioate and guanosine 5'-O- phosphorothioate to the corresponding nucleoside 5'-O-phosphates with concomitant release of hydrogen sulfide. In addition, functions as scaffolding protein that modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex and by the complex formed with MITF and CTNNB1. Modulates p53/TP53 levels and p53/TP53-mediated apoptosis. Modulates proteasomal degradation of target proteins by the SCF (SKP2-CUL1-F-box protein) E3 ubiquitin- protein ligase complex. {ECO:0000269|PubMed:15703176, ECO:0000269|PubMed:16014379, ECO:0000269|PubMed:16835243, ECO:0000269|PubMed:19112177, ECO:0000269|PubMed:22329685, ECO:0000269|PubMed:22647378, ECO:0000269|PubMed:9323207}.;

Recessive Scores

pRec: 0.216

Intolerance Scores

LoFtool: 0.575
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.645

Gene Damage Prediction

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