chr5-131160446-C-G

Variant names:

• chr5-131160446-C-G
• rs2551038
• NM_005340.7:c.217-835G>C

Variant summary

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

The NM_005340.7(HINT1):​c.217-835G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 152,218 control chromosomes in the GnomAD database, including 62,480 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 0.90 (62480 hom., cov: 32)
• Consequence: HINT1 NM_005340.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 10 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HINT1	NM_005340.7	c.217-835G>C		intron_variant	Intron 2 of 2	ENST00000304043.10	NP_005331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HINT1	ENST00000304043.10	c.217-835G>C		intron_variant	Intron 2 of 2	1	NM_005340.7	ENSP00000304229.5

Frequencies

GnomAD3 genomes AF: 0.904 AC: 137466 AN: 152100 Hom.: 62412 Cov.: 32

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.880

Gnomad OTH AF: 0.903

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

GnomAD4 genome AF: 0.904 AC: 137593 AN: 152218 Hom.: 62480 Cov.: 32 AF XY: 0.901 AC XY: 67019 AN XY: 74408

African (AFR) AF: 0.979 AC: 40703 AN: 41566

American (AMR) AF: 0.936 AC: 14311 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2977 AN: 3470

East Asian (EAS) AF: 0.797 AC: 4122 AN: 5170

South Asian (SAS) AF: 0.906 AC: 4365 AN: 4818

European-Finnish (FIN) AF: 0.785 AC: 8310 AN: 10588

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.880 AC: 59837 AN: 68006

Other (OTH) AF: 0.904 AC: 1901 AN: 2104

Alfa AF: 0.865 Hom.: 3159

Bravo AF: 0.919

Asia WGS AF: 0.885 AC: 3078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.97
DANN	Benign	0.51
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2551038; hg19: chr5-130496139;