rs78949626

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-131162671-A-G
• chr5-131162671-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005340.7(HINT1):​c.117T>C​(p.Leu39Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,597,166 control chromosomes in the GnomAD database, including 11 homozygotes. 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: 𝑓 0.0039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: HINT1 NM_005340.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005710304).
• BP6: Variant 5-131162671-A-G is Benign according to our data. Variant chr5-131162671-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 477392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.254 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00385 (587/152320) while in subpopulation AFR AF = 0.0089 (370/41580). AF 95% confidence interval is 0.00815. There are 1 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	NM_005340.7	MANE Select	c.117T>C	p.Leu39Leu	synonymous	Exon 2 of 3	NP_005331.1	P49773
	HINT1	NM_001437949.1		c.117T>C	p.Leu39Leu	synonymous	Exon 2 of 3	NP_001424878.1	D6RD60
	HINT1	NM_001437950.1		c.117T>C	p.Leu39Leu	synonymous	Exon 2 of 2	NP_001424879.1	D6RE99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	ENST00000304043.10	TSL:1 MANE Select	c.117T>C	p.Leu39Leu	synonymous	Exon 2 of 3	ENSP00000304229.5	P49773
	HINT1	ENST00000508495.5	TSL:1	n.117T>C		non_coding_transcript_exon	Exon 2 of 4	ENSP00000424974.1	D6REP8
	HINT1	ENST00000513012.2	TSL:4	c.152T>C	p.Leu51Ser	missense	Exon 2 of 2	ENSP00000422444.1	D6RC06

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00888

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00203 AC: 509 AN: 250338 AF XY: 0.00187

Gnomad AFR exome AF: 0.00981

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00767

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00125 AC: 1799 AN: 1444846 Hom.: 10 Cov.: 28 AF XY: 0.00126 AC XY: 904 AN XY: 719800

African (AFR) AF: 0.0110 AC: 365 AN: 33070

American (AMR) AF: 0.00364 AC: 162 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00731 AC: 190 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.0000934 AC: 8 AN: 85658

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.0121 AC: 63 AN: 5198

European-Non Finnish (NFE) AF: 0.000728 AC: 799 AN: 1097672

Other (OTH) AF: 0.00353 AC: 211 AN: 59800

GnomAD4 genome AF: 0.00385 AC: 587 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74482

African (AFR) AF: 0.00890 AC: 370 AN: 41580

American (AMR) AF: 0.00589 AC: 90 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00390 Hom.: 2

Bravo AF: 0.00425

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00194 AC: 236

EpiCase AF: 0.00174

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive axonal neuropathy with neuromyotonia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	8.6
DANN	Uncertain	0.99
Eigen	Benign	0.051
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.51	T
PhyloP100		0.25
PROVEAN	Benign	0.69	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.082	T
Vest4		0.31
MVP		0.72
ClinPred		0.063	T
GERP RS		2.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=79/21	polymorphism

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: rs78949626; hg19: chr5-130498364;