chr12-100357146-T-C

Variant names:

• chr12-100357146-T-C
• rs60738448
• NM_139319.3:c.-246T>C

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.-246T>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 0.00131 in 455,828 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: SLC17A8 NM_139319.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.29

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 (BayesDel_noAF=-0.65).
• BP6: Variant 12-100357146-T-C is Benign according to our data. Variant chr12-100357146-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 883122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A8	NM_139319.3	c.-246T>C		5_prime_UTR_variant	Exon 1 of 12	ENST00000323346.10	NP_647480.1
SLC17A8	NM_001145288.2	c.-246T>C		5_prime_UTR_variant	Exon 1 of 11		NP_001138760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A8	ENST00000323346	c.-246T>C		5_prime_UTR_variant	Exon 1 of 12	1	NM_139319.3	ENSP00000316909.4
SLC17A8	ENST00000392989.3	c.-246T>C		upstream_gene_variant		1		ENSP00000376715.3

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00946

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00143 AC: 433 AN: 303572 Hom.: 1 Cov.: 0 AF XY: 0.00120 AC XY: 197 AN XY: 163912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.000416

Gnomad4 FIN exome AF: 0.00285

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74446

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00949

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.00153

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 25 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.82

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: rs60738448; hg19: chr12-100750924;