rs149782619

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The ENST00000304043.10(HINT1):c.110G>C(p.Arg37Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

HINT1
ENST00000304043.10 missense, splice_region

Scores

Splicing: ADA: 0.0001172

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.185

Variant links:

Genes affected

HINT1 (HGNC:4912): (histidine triad nucleotide binding protein 1) 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]

HINT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Adenosine 5'-monophosphoramidase HINT1 (size 124) in uniprot entity HINT1_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in ENST00000304043.10

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-131165096-C-G is Pathogenic according to our data. Variant chr5-131165096-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 37312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-131165096-C-G is described in Lovd as [Likely_pathogenic]. Variant chr5-131165096-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HINT1	NM_005340.7 linkuse as main transcript	c.110G>C	p.Arg37Pro	missense_variant, splice_region_variant	1/3	ENST00000304043.10	NP_005331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HINT1	ENST00000304043.10 linkuse as main transcript	c.110G>C	p.Arg37Pro	missense_variant, splice_region_variant	1/3	1	NM_005340.7	ENSP00000304229	P1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000260

AC:

AN:

250326

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000893

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000212

AC:

310

AN:

1461362

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000772

Gnomad4 NFE exome

AF:

0.000235

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000315

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive axonal neuropathy with neuromyotonia

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 14, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 02, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 02, 2024	Criteria applied: PM3_VSTR,PS4_SUP,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.030%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000037312). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 22961002, 22961002, 26182879, 27549087). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 37 of the HINT1 protein (p.Arg37Pro). This variant is present in population databases (rs149782619, gnomAD 0.09%). This missense change has been observed in individuals with clinical features of distal hereditary motor neuropathy (PMID: 22961002, 25342199, 26182879, 27549087). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37312). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.110G>C (p.Arg37Pro) variant in HINT1 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with neuromyotonia and axonal neuropathy (Zimon et al., 2012; Laššuthová et al., 2015; Jerath et al., 2015; Laššuthová et al., 2016). It has also been observed to segregate with disease in related individuals. Functional studies demonstrate this variant to cause loss of enzyme function (Zimon et al., 2012). This variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Arg37Pro in HINT1 is predicted as conserved by PhyloP across 100 vertebrates. The amino acid Arg at position 37 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2022	Published functional studies demonstrate loss of enzyme function in the homozygous state (Zimon et al., 2012); Reported as a founder mutation in the Czech population, accounting for 95% of pathogenic alleles (Lassuthova et al., 2015).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26182879, 32709422, 22961002, 24918641, 25342199, 26194197, 23043279, 27549087, 29787766, 31787464, 31848916, 34562060, 33726816, 34694653, 33663550) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	HINT1: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2022

The c.110G>C (p.R37P) alteration is located in exon 1 (coding exon 1) of the HINT1 gene. This alteration results from a G to C substitution at nucleotide position 110, causing the arginine (R) at amino acid position 37 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD), the HINT1 c.110G>C alteration was observed in 0.03% (85/281,678) of total alleles studied. The p.R37P alteration, one of three founder mutations and considered to be the most common, has been reported in homozygous and compound heterozygous individuals with autosomal recessive axonal neuropathy with neuromyotonia (Zimo, 2012; La&scaron;&scaron;uthová, 2015; Jerath, 2015; Shchagina, 2020). This amino acid position is poorly conserved in available vertebrate species. Protein contain p.R37P fails to form functional dimers and exists as monomers, which showed significant loss of secondary structure compared to wild type and showed reduced near UV-absorption indicating incorrect or improper folding (Shah, 2018). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Peripheral neuropathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;.;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.95

D;D;D;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.2

L;.;.;.

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.095

T;D;T;D

Sift4G

Benign

0.18

T;T;T;D

Polyphen

0.26

B;.;.;.

Vest4

0.62

MVP

0.76

MPC

0.89

ClinPred

0.90

GERP RS

-0.94

Varity_R

0.95

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.094

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over