12-100357174-T-C

Position:

• chr12-100357174-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139319.3(SLC17A8):​c.-218T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 511,460 control chromosomes in the GnomAD database, including 8,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2578 hom., cov: 32)
  • Exomes 𝑓: 0.17 (6158 hom.)
• Consequence: SLC17A8 NM_139319.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.117

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-100357174-T-C is Benign according to our data. Variant chr12-100357174-T-C is described in ClinVar as [Benign]. Clinvar id is 306619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A8	NM_139319.3	c.-218T>C		5_prime_UTR_variant	1/12	ENST00000323346.10	NP_647480.1
SLC17A8	NM_001145288.2	c.-218T>C		5_prime_UTR_variant	1/11		NP_001138760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A8	ENST00000323346.10	c.-218T>C		5_prime_UTR_variant	1/12	1	NM_139319.3	ENSP00000316909	P1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26785 AN: 151990 Hom.: 2575 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.00426

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.173 AC: 61991 AN: 359352 Hom.: 6158 Cov.: 0 AF XY: 0.170 AC XY: 32892 AN XY: 193610

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.00332

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.176 AC: 26810 AN: 152108 Hom.: 2578 Cov.: 32 AF XY: 0.170 AC XY: 12663 AN XY: 74370

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.00427

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.189

Alfa AF: 0.203 Hom.: 2750

Bravo AF: 0.178

Asia WGS AF: 0.0810 AC: 282 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2019	- -

Autosomal dominant nonsyndromic hearing loss 25 Benign:1

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 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	-0.87
CADD	Benign	4.3
DANN	Benign	0.54

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: rs10860582; hg19: chr12-100750952;