rs4696

Variant names:

• chr5-131165149-A-G
• rs4696
• NM_005340.7:c.57T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005340.7(HINT1):​c.57T>C​(p.Phe19Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,612,466 control chromosomes in the GnomAD database, including 5,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2642 hom., cov: 33)
  • Exomes 𝑓: 0.038 (3094 hom.)
• Consequence: HINT1 NM_005340.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.763
• Publications: 16 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 5-131165149-A-G is Benign according to our data. Variant chr5-131165149-A-G is described in ClinVar as Benign. ClinVar VariationId is 259745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.763 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 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.57T>C	p.Phe19Phe	synonymous	Exon 1 of 3	NP_005331.1
	HINT1	NM_001437949.1		c.57T>C	p.Phe19Phe	synonymous	Exon 1 of 3	NP_001424878.1
	HINT1	NM_001437950.1		c.57T>C	p.Phe19Phe	synonymous	Exon 1 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.57T>C	p.Phe19Phe	synonymous	Exon 1 of 3	ENSP00000304229.5
	HINT1	ENST00000508495.5	TSL:1	n.57T>C		non_coding_transcript_exon	Exon 1 of 4	ENSP00000424974.1
	HINT1	ENST00000675100.1		c.57T>C	p.Phe19Phe	synonymous	Exon 1 of 3	ENSP00000502350.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17954 AN: 152146 Hom.: 2639 Cov.: 33

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0974

GnomAD2 exomes AF: 0.0504 AC: 12571 AN: 249504 AF XY: 0.0438

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00843

Gnomad NFE exome AF: 0.0325

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0379 AC: 55399 AN: 1460202 Hom.: 3094 Cov.: 32 AF XY: 0.0368 AC XY: 26761 AN XY: 726506

African (AFR) AF: 0.354 AC: 11855 AN: 33454

American (AMR) AF: 0.0414 AC: 1852 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 2234 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39690

South Asian (SAS) AF: 0.0162 AC: 1399 AN: 86254

European-Finnish (FIN) AF: 0.00998 AC: 519 AN: 51984

Middle Eastern (MID) AF: 0.114 AC: 654 AN: 5752

European-Non Finnish (NFE) AF: 0.0302 AC: 33602 AN: 1111868

Other (OTH) AF: 0.0544 AC: 3281 AN: 60360

GnomAD4 genome AF: 0.118 AC: 17990 AN: 152264 Hom.: 2642 Cov.: 33 AF XY: 0.114 AC XY: 8462 AN XY: 74450

African (AFR) AF: 0.344 AC: 14294 AN: 41528

American (AMR) AF: 0.0576 AC: 882 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 306 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4832

European-Finnish (FIN) AF: 0.00781 AC: 83 AN: 10626

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0310 AC: 2111 AN: 68012

Other (OTH) AF: 0.0964 AC: 204 AN: 2116

Alfa AF: 0.0702 Hom.: 430

Bravo AF: 0.133

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0368

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive axonal neuropathy with neuromyotonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.76
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs4696; hg19: chr5-130500842;