NM_005340.7:c.216+837A>G

Variant names:

• chr5-131161735-T-C
• rs3864283
• NM_005340.7:c.216+837A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005340.7(HINT1):​c.216+837A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 152,152 control chromosomes in the GnomAD database, including 14,275 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (14275 hom., cov: 32)
• Consequence: HINT1 NM_005340.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 11 publications found

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, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	NM_005340.7	MANE Select	c.216+837A>G		intron	N/A	NP_005331.1
	HINT1	NM_001437949.1		c.*647A>G		3_prime_UTR	Exon 3 of 3	NP_001424878.1
	HINT1	NM_001437950.1		c.*816A>G		3_prime_UTR	Exon 2 of 2	NP_001424879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	ENST00000304043.10	TSL:1 MANE Select	c.216+837A>G		intron	N/A	ENSP00000304229.5
	HINT1	ENST00000508495.5	TSL:1	n.216+837A>G		intron	N/A	ENSP00000424974.1
	HINT1	ENST00000675491.1		c.*647A>G		3_prime_UTR	Exon 3 of 3	ENSP00000502370.1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58156 AN: 152032 Hom.: 14242 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.349

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.383 AC: 58225 AN: 152152 Hom.: 14275 Cov.: 32 AF XY: 0.378 AC XY: 28113 AN XY: 74388

African (AFR) AF: 0.704 AC: 29229 AN: 41502

American (AMR) AF: 0.261 AC: 3994 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 956 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1123 AN: 5190

South Asian (SAS) AF: 0.278 AC: 1340 AN: 4826

European-Finnish (FIN) AF: 0.285 AC: 3013 AN: 10566

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17495 AN: 67994

Other (OTH) AF: 0.349 AC: 737 AN: 2114

Alfa AF: 0.283 Hom.: 4173

Bravo AF: 0.392

Asia WGS AF: 0.321 AC: 1117 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.73
DANN	Benign	0.56
PhyloP100		-1.5
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs3864283; hg19: chr5-130497428;