rs78949626

chr5-131162671-A-Gchr5-131162671-A-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_005340.7(HINT1):c.117T>C(p.Leu39=) 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:6
• Conservation: PhyloP100: 0.254

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]

ACMG classification

Verdict is Benign. Variant got -17 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 [Likely_benign]. Clinvar id is 477392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-131162671-A-G is described in Lovd as [Benign]. Variant chr5-131162671-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HINT1	NM_005340.7	c.117T>C	p.Leu39=	synonymous_variant	2/3	ENST00000304043.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HINT1	ENST00000304043.10	c.117T>C	p.Leu39=	synonymous_variant	2/3	1	NM_005340.7	P1

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

GnomAD3 exomes AF: 0.00203 AC: 509 AN: 250338 Hom.: 1 AF XY: 0.00187 AC XY: 253 AN XY: 135332

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 SAS exome AF: 0.0000989

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

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000934

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000728

Gnomad4 OTH exome AF: 0.00353

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

Gnomad4 AFR AF: 0.00890

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00298 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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	HINT1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal recessive axonal neuropathy with neuromyotonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	D;D;D;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs78949626; hg19: chr5-130498364;