rs386519465

chr12-100357414-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.20

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 -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 GnomAd at 715 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A8	ENST00000323346.10	c.23C>T	p.Thr8Ile	missense_variant	1/12	1	NM_139319.3	P1
SLC17A8	ENST00000392989.3	c.23C>T	p.Thr8Ile	missense_variant	1/11	1

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 152162 Hom.: 4 Cov.: 32

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.: 0 AF XY: 0.00111 AC XY: 151 AN XY: 135906

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.: 4 Cov.: 29 AF XY: 0.000586 AC XY: 426 AN XY: 726398

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.: 4 Cov.: 32 AF XY: 0.00482 AC XY: 359 AN XY: 74476

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.: 2

Bravo AF: 0.00542

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
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	T
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

Other links and lift over

dbSNP: rs45610843; hg19: chr12-100751192;