chr12-100404104-G-T

Position:

chr12-100404104-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_139319.3(SLC17A8):c.1120G>T(p.Ala374Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,614,112 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00092 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 4 hom. )

Consequence

SLC17A8
NM_139319.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 10.0

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:

SLC17A8 (HGNC:):

SLC17A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022830486).

BP6

Variant 12-100404104-G-T is Benign according to our data. Variant chr12-100404104-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225471.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAd4 at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A8	NM_139319.3 linkuse as main transcript	c.1120G>T	p.Ala374Ser	missense_variant	9/12	ENST00000323346.10	NP_647480.1	Q8NDX2-1
SLC17A8	NM_001145288.2 linkuse as main transcript	c.970G>T	p.Ala324Ser	missense_variant	8/11		NP_001138760.1	Q8NDX2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC17A8	ENST00000323346.10 linkuse as main transcript	c.1120G>T	p.Ala374Ser	missense_variant	9/12	1	NM_139319.3	ENSP00000316909.4	Q8NDX2-1
SLC17A8	ENST00000392989.3 linkuse as main transcript	c.970G>T	p.Ala324Ser	missense_variant	8/11	1		ENSP00000376715.3	Q8NDX2-2
SLC17A8	ENST00000547922.1 linkuse as main transcript	n.195G>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00577

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00538

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00125

AC:

314

AN:

251366

Hom.:

AF XY:

0.00135

AC XY:

183

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00544

Gnomad SAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000504

AC:

737

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000573

AC XY:

417

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00403

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.00453

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152270

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00578

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00538

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000530

Hom.:

Bravo

AF:

0.000302

ExAC

AF:

0.00124

AC:

151

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 25

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 22, 2020	A heterozygous missense variation in exon 9 of the SLC17A5 gene that results in the amino acid substitution of Serine for Alanine at codon 374 was detected. The observed variant c.1120G>T (p.Ala374Ser) has a minor allele frequency of 0.2% and 0.12% in the 1000 genomes and ExAC databases respectively. The observed variant has previously been reported in a patient affected with deafness (Miyagawa et al. 2013) and is reported as a variant of uncertain significance in the ClinVar database. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	This variant is associated with the following publications: (PMID: 23967202, 30245029) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 08, 2023	- -

SLC17A8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2022

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.64

MPC

0.61

ClinPred

0.081

GERP RS

5.6

Varity_R

0.71

gMVP

0.77

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