12-100357414-C-T

Position:

chr12-100357414-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_139319.3(SLC17A8):c.23C>T(p.Thr8Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,612,098 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 4 hom. )

Consequence

SLC17A8
NM_139319.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

SLC17A8 (HGNC:20151): (solute carrier family 17 member 8) This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

SLC17A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003473699).

BP6

Variant 12-100357414-C-T is Benign according to our data. Variant chr12-100357414-C-T is described in ClinVar as [Benign]. Clinvar id is 178632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-100357414-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 713 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A8	NM_139319.3 linkuse as main transcript	c.23C>T	p.Thr8Ile	missense_variant	1/12	ENST00000323346.10	NP_647480.1
SLC17A8	NM_001145288.2 linkuse as main transcript	c.23C>T	p.Thr8Ile	missense_variant	1/11		NP_001138760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A8	ENST00000323346.10 linkuse as main transcript	c.23C>T	p.Thr8Ile	missense_variant	1/12	1	NM_139319.3	ENSP00000316909	P1	Q8NDX2-1
SLC17A8	ENST00000392989.3 linkuse as main transcript	c.23C>T	p.Thr8Ile	missense_variant	1/11	1		ENSP00000376715		Q8NDX2-2

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

715

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00153

AC:

384

AN:

251426

Hom.:

AF XY:

0.00111

AC XY:

151

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0152

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000658

AC:

961

AN:

1459818

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

426

AN XY:

726398

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.00174

GnomAD4 genome

AF:

0.00468

AC:

713

AN:

152280

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

359

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0148

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.00542

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00178

AC:

216

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Thr8Ile in Exon 01 of SLC17A8: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (56/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs45610843). -

SLC17A8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nonsyndromic hearing loss 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.055

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.087

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.044

D;D

Polyphen

0.097

B;B

Vest4

0.13

MVP

0.35

MPC

0.19

ClinPred

0.012

GERP RS

4.2

Varity_R

0.10

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over