rs11568531

Variant names:

• chr12-100390997-C-A
• rs11568531
• NM_139319.3:c.355-4C>A

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00004619
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.66
• Publications: 4 publications found

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]

SLC17A8 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 25

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 165242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 965 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139319.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	NM_139319.3	MANE Select	c.355-4C>A		splice_region intron	N/A	NP_647480.1
	SLC17A8	NM_001145288.2		c.355-4C>A		splice_region intron	N/A	NP_001138760.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	ENST00000323346.10	TSL:1 MANE Select	c.355-4C>A		splice_region intron	N/A	ENSP00000316909.4
	SLC17A8	ENST00000392989.3	TSL:1	c.355-4C>A		splice_region intron	N/A	ENSP00000376715.3
	SLC17A8	ENST00000874772.1		c.355-4C>A		splice_region intron	N/A	ENSP00000544831.1

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

GnomAD2 exomes AF: 0.00338 AC: 850 AN: 251340 AF XY: 0.00292

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 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

African (AFR) AF: 0.0194 AC: 642 AN: 33064

American (AMR) AF: 0.00624 AC: 279 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00119 AC: 102 AN: 85864

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.0136 AC: 78 AN: 5732

European-Non Finnish (NFE) AF: 0.000880 AC: 963 AN: 1094450

Other (OTH) AF: 0.00445 AC: 266 AN: 59760

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

African (AFR) AF: 0.0165 AC: 687 AN: 41562

American (AMR) AF: 0.00739 AC: 113 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68020

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00423 Hom.: 2

Bravo AF: 0.00796

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal dominant nonsyndromic hearing loss 25 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.9
DANN	Benign	0.67
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11568531; hg19: chr12-100784775;