rs11110359

chr12-100380770-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_139319.3(SLC17A8):c.171G>A(p.Thr57=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,614,034 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (46 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (400 hom.)
• Consequence: SLC17A8 NM_139319.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.70

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-100380770-G-A is Benign according to our data. Variant chr12-100380770-G-A is described in ClinVar as [Benign]. Clinvar id is 47882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A8	NM_139319.3	c.171G>A	p.Thr57=	synonymous_variant	2/12	ENST00000323346.10
SLC17A8	NM_001145288.2	c.171G>A	p.Thr57=	synonymous_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A8	ENST00000323346.10	c.171G>A	p.Thr57=	synonymous_variant	2/12	1	NM_139319.3	P1
SLC17A8	ENST00000392989.3	c.171G>A	p.Thr57=	synonymous_variant	2/11	1

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 939 AN: 152028 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00889

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0112 AC: 2812 AN: 251430 Hom.: 146 AF XY: 0.0104 AC XY: 1416 AN XY: 135896

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.123

Gnomad SAS exome AF: 0.00349

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00502 AC: 7337 AN: 1461888 Hom.: 400 Cov.: 31 AF XY: 0.00504 AC XY: 3664 AN XY: 727246

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.00972

Gnomad4 NFE exome AF: 0.000485

Gnomad4 OTH exome AF: 0.00780

GnomAD4 genome AF: 0.00619 AC: 942 AN: 152146 Hom.: 46 Cov.: 31 AF XY: 0.00714 AC XY: 531 AN XY: 74374

Gnomad4 AFR AF: 0.000675

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00889

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00615

Asia WGS AF: 0.0570 AC: 196 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr57Thr in Exon 02 of SLC17A8: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 14.2% (17/120) of c hromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/ projects/SNP; rs11110359). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

SLC17A8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

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
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.034
Dann	Benign	0.52

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: rs11110359; hg19: chr12-100774548; COSMIC: COSV60121609;