Genetic Variant NM_005340.7:c.281A>G (chr5-131159547-T-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_005340.7(HINT1):c.281A>G(p.Tyr94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HINT1
NM_005340.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Gamstorp-Wohlfart syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

HINT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_005340.7

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.44207 (below the threshold of 3.09). Trascript score misZ: 0.49961 (below the threshold of 3.09). GenCC associations: The gene is linked to Gamstorp-Wohlfart syndrome, Charcot-Marie-Tooth disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005340.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HINT1	NM_005340.7	MANE Select	c.281A>G	p.Tyr94Cys	missense	Exon 3 of 3	NP_005331.1	P49773
HINT1	NM_001437949.1		c.*2835A>G		3_prime_UTR	Exon 3 of 3	NP_001424878.1	D6RD60
HINT1	NM_001437950.1		c.*3004A>G		3_prime_UTR	Exon 2 of 2	NP_001424879.1	D6RE99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HINT1	ENST00000304043.10	TSL:1 MANE Select	c.281A>G	p.Tyr94Cys	missense	Exon 3 of 3	ENSP00000304229.5	P49773
HINT1	ENST00000508495.5	TSL:1	n.*233A>G		non_coding_transcript_exon	Exon 4 of 4	ENSP00000424974.1	D6REP8
HINT1	ENST00000508495.5	TSL:1	n.*233A>G		3_prime_UTR	Exon 4 of 4	ENSP00000424974.1	D6REP8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive axonal neuropathy with neuromyotonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.1

PhyloP100

1.8

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.66

MutPred

0.80

Gain of ubiquitination at K92 (P = 0.0818)

MVP

0.95

MPC

1.5

ClinPred

1.0

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.89

Mutation Taster

=18/82

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over