5-131159544-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_005340.7(HINT1):c.284G>A(p.Arg95Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

HINT1
NM_005340.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.18

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a domain HIT (size 108) in uniprot entity HINT1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_005340.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 5-131159544-C-T is Pathogenic according to our data. Variant chr5-131159544-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 811058.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HINT1	NM_005340.7 link	c.284G>A	p.Arg95Gln	missense_variant	Exon 3 of 3	ENST00000304043.10	NP_005331.1	P49773A0A384NPU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HINT1	ENST00000304043.10 link	c.284G>A	p.Arg95Gln	missense_variant	Exon 3 of 3	1	NM_005340.7	ENSP00000304229.5		P49773

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251382

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000602

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive axonal neuropathy with neuromyotonia

Pathogenic:1Uncertain:1

Aug 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HINT1 p.Arg95Gln variant (rs373197800), to our knowledge, has not been reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.0004% (1/275,000 alleles) in the Genome Aggregation Database. The arginine at codon 95 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. However, a nearby variant, p.Gly93Asp, has been observed in trans with a pathogenic variant, p.Gln62Ter, in two siblings with neuromytonia (Hahn 1991 and Zimon 2012), suggesting this region of HINT1 is critical for protein function. However, based on the available information, the clinical significance of the p.Arg95Gln variant is uncertain. Zimon M et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012 Oct;44(10):1080-3. Hahn AF et al. Neuromyotonia in hereditary motor neuropathy. J Neurol Neurosurg Psychiatry. 1991 Mar;54(3):230-5. -

Jul 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects HINT1 function (PMID: 33663550). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 811058). This missense change has been observed in individual(s) with clinical features of HINT1-related conditions (PMID: 33663550). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs373197800, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 95 of the HINT1 protein (p.Arg95Gln). -

not provided

Uncertain:1

Dec 11, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.85

Sift

Benign

0.038

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.89

MVP

0.95

MPC

1.2

ClinPred

0.98

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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