NM_005340.7:c.117T>A

Variant names:

• chr5-131162671-A-T
• rs78949626
• NM_005340.7:c.117T>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005340.7(HINT1):​c.117T>A​(p.Leu39Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,444,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L39L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HINT1 NM_005340.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.254
• Publications: 5 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.209167).
• BP6: Variant 5-131162671-A-T is Benign according to our data. Variant chr5-131162671-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 838803.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.254 with no splicing effect.

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.117T>A	p.Leu39Leu	synonymous	Exon 2 of 3	NP_005331.1
	HINT1	NM_001437949.1		c.117T>A	p.Leu39Leu	synonymous	Exon 2 of 3	NP_001424878.1
	HINT1	NM_001437950.1		c.117T>A	p.Leu39Leu	synonymous	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.117T>A	p.Leu39Leu	synonymous	Exon 2 of 3	ENSP00000304229.5
	HINT1	ENST00000508495.5	TSL:1	n.117T>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000424974.1
	HINT1	ENST00000513012.2	TSL:4	c.152T>A	p.Leu51*	stop_gained	Exon 2 of 2	ENSP00000422444.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1444864 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 719810

African (AFR) AF: 0.00 AC: 0 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1097682

Other (OTH) AF: 0.00 AC: 0 AN: 59802

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive axonal neuropathy with neuromyotonia Benign:1

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.5
DANN	Uncertain	0.99
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		0.25
Vest4		0.71
GERP RS		2.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=71/129	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78949626; hg19: chr5-130498364;