rs11568531

Positions:

• chr12-100390997-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_139319.3(SLC17A8):​c.355-4C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,594,854 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (20 hom.)
• Consequence: SLC17A8 NM_139319.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004619
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-100390997-C-A is Benign according to our data. Variant chr12-100390997-C-A is described in ClinVar as [Benign]. Clinvar id is 165242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-100390997-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00634 (965/152298) while in subpopulation AFR AF= 0.0165 (687/41562). AF 95% confidence interval is 0.0155. There are 8 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 965 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A8	NM_139319.3	c.355-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000323346.10
SLC17A8	NM_001145288.2	c.355-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A8	ENST00000323346.10	c.355-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_139319.3	P1
SLC17A8	ENST00000392989.3	c.355-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 964 AN: 152180 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00338 AC: 850 AN: 251340 Hom.: 6 AF XY: 0.00292 AC XY: 397 AN XY: 135840

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00184 AC: 2649 AN: 1442556 Hom.: 20 Cov.: 28 AF XY: 0.00179 AC XY: 1288 AN XY: 719148

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000880

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00634 AC: 965 AN: 152298 Hom.: 8 Cov.: 31 AF XY: 0.00565 AC XY: 421 AN XY: 74484

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00432 Hom.: 2

Bravo AF: 0.00796

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00207

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	GeneDx	Feb 02, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	355-4C>A in Intron 02 of SLC17A8: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 1.7% (62/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs11568531). -

Autosomal dominant nonsyndromic hearing loss 25 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 08, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.9
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
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: rs11568531; hg19: chr12-100784775;