HINT1

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

Basic information

Region (hg38): 5:131155383-131224468

Previous symbols: [ "PRKCNH1", "HINT" ]

Links

ENSG00000169567 ∙ NCBI:3094 ∙ OMIM:601314 ∙ HGNC:4912 ∙ Uniprot:P49773 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Gamstorp-Wohlfart syndrome (Definitive), mode of inheritance: AR
• Gamstorp-Wohlfart syndrome (Strong), mode of inheritance: AR
• Gamstorp-Wohlfart syndrome (Strong), mode of inheritance: AR
• Gamstorp-Wohlfart syndrome (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neuromyotonia and axonal neuropathy, autosomal recessive	AR	General	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	Musculoskeletal	22961002

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HINT1 gene.

• Autosomal recessive axonal neuropathy with neuromyotonia (11 variants)
• not provided (4 variants)
• Charcot-Marie-Tooth disease (2 variants)
• Inborn genetic diseases (2 variants)
• Peripheral neuropathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HINT1 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			2	14	1	17
missense	1	4	40			45
nonsense	5		1			6
start loss	1					1
frameshift	6		1			7
inframe indel						0
splice donor/acceptor (+/-2bp)		2				2
splice region			1	1		2
non coding				13	12	25
Total	13	6	44	27	13

Highest pathogenic variant AF is 0.000315

Variants in HINT1

This is a list of pathogenic ClinVar variants found in the HINT1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-131159434-C-A		not specified	Likely benign (Jan 12, 2016)
5-131159450-A-T		Autosomal recessive axonal neuropathy with neuromyotonia	Likely benign (Oct 20, 2023)
5-131159452-CA-C		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (Jun 29, 2020)
5-131159459-C-T		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (Nov 04, 2020)
5-131159460-C-T		Charcot-Marie-Tooth disease • Autosomal recessive axonal neuropathy with neuromyotonia	Pathogenic (Dec 01, 2020)
5-131159463-T-A		Autosomal recessive axonal neuropathy with neuromyotonia • Inborn genetic diseases	Uncertain significance (Mar 15, 2022)
5-131159473-G-A		Autosomal recessive axonal neuropathy with neuromyotonia	Conflicting classifications of pathogenicity (Dec 01, 2020)
5-131159473-G-C		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (May 01, 2022)
5-131159486-A-G		Autosomal recessive axonal neuropathy with neuromyotonia	Likely benign (Jun 03, 2023)
5-131159487-T-C		Charcot-Marie-Tooth disease	Uncertain significance (-)
5-131159494-G-T		Autosomal recessive axonal neuropathy with neuromyotonia	Likely pathogenic (Aug 02, 2024)
5-131159497-C-T		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (Dec 06, 2023)
5-131159498-G-A		Autosomal recessive axonal neuropathy with neuromyotonia • not specified • Inborn genetic diseases • HINT1-related disorder	Benign/Likely benign (Dec 31, 2023)
5-131159497-C-CGT		Autosomal recessive axonal neuropathy with neuromyotonia	Pathogenic (Nov 07, 2022)
5-131159502-T-C		Inborn genetic diseases	Uncertain significance (Mar 08, 2022)
5-131159512-G-A		Charcot-Marie-Tooth disease • Autosomal recessive axonal neuropathy with neuromyotonia	Pathogenic (Mar 12, 2022)
5-131159526-C-T		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (Feb 24, 2022)
5-131159529-T-C		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (May 18, 2022)
5-131159535-AC-A		Autosomal recessive axonal neuropathy with neuromyotonia	Pathogenic (Jan 03, 2022)
5-131159536-C-T		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (Jan 14, 2019)
5-131159539-C-T		Autosomal recessive axonal neuropathy with neuromyotonia	Likely pathogenic (Mar 29, 2018)
5-131159544-C-T		Autosomal recessive axonal neuropathy with neuromyotonia	Conflicting classifications of pathogenicity (Jul 22, 2023)
5-131159545-G-A		Autosomal recessive axonal neuropathy with neuromyotonia	Pathogenic (Mar 09, 2020)
5-131159547-T-C		Autosomal recessive axonal neuropathy with neuromyotonia	Uncertain significance (Apr 22, 2023)
5-131159550-C-A		Autosomal recessive axonal neuropathy with neuromyotonia	Likely pathogenic (Jan 05, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HINT1	protein_coding	protein_coding	ENST00000304043	3	12709

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00182	0.498	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.442	63	73.7	0.855	0.00000349	828
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000545	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000528	0.0000527
Middle Eastern	0.0000545	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.305
• hipred: Y
• hipred_score: 0.514
• ghis: 0.659

Essentials

• essential_gene_CRISPR: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.645

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hint1
• Phenotype: neoplasm; hematopoietic system phenotype; normal phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• 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
• Cellular component: histone deacetylase complex;nucleus;cytosol;cytoskeleton;plasma membrane;extracellular exosome
• Molecular function: nucleotide binding;protein kinase C binding;hydrolase activity