rs11110359

Variant names:

• chr12-100380770-G-A
• rs11110359
• NM_139319.3:c.171G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_139319.3(SLC17A8):​c.171G>A​(p.Thr57Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,614,034 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (46 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (400 hom.)
• Consequence: SLC17A8 NM_139319.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.70
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-100380770-G-A is Benign according to our data. Variant chr12-100380770-G-A is described in ClinVar as Benign. ClinVar VariationId is 47882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

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.171G>A	p.Thr57Thr	synonymous	Exon 2 of 12	NP_647480.1	Q8NDX2-1
	SLC17A8	NM_001145288.2		c.171G>A	p.Thr57Thr	synonymous	Exon 2 of 11	NP_001138760.1	Q8NDX2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	ENST00000323346.10	TSL:1 MANE Select	c.171G>A	p.Thr57Thr	synonymous	Exon 2 of 12	ENSP00000316909.4	Q8NDX2-1
	SLC17A8	ENST00000392989.3	TSL:1	c.171G>A	p.Thr57Thr	synonymous	Exon 2 of 11	ENSP00000376715.3	Q8NDX2-2
	SLC17A8	ENST00000874772.1		c.171G>A	p.Thr57Thr	synonymous	Exon 3 of 13	ENSP00000544831.1

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 939 AN: 152028 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00889

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0112 AC: 2812 AN: 251430 AF XY: 0.0104

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00502 AC: 7337 AN: 1461888 Hom.: 400 Cov.: 31 AF XY: 0.00504 AC XY: 3664 AN XY: 727246

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00134 AC: 60 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.136 AC: 5399 AN: 39696

South Asian (SAS) AF: 0.00364 AC: 314 AN: 86258

European-Finnish (FIN) AF: 0.00972 AC: 519 AN: 53420

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000485 AC: 539 AN: 1112010

Other (OTH) AF: 0.00780 AC: 471 AN: 60396

GnomAD4 genome AF: 0.00619 AC: 942 AN: 152146 Hom.: 46 Cov.: 31 AF XY: 0.00714 AC XY: 531 AN XY: 74374

African (AFR) AF: 0.000675 AC: 28 AN: 41506

American (AMR) AF: 0.00262 AC: 40 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.125 AC: 646 AN: 5162

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.00889 AC: 94 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68000

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00615

Asia WGS AF: 0.0570 AC: 196 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 25 (1)
-	-	1	SLC17A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.034
DANN	Benign	0.52
PhyloP100		-4.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11110359; hg19: chr12-100774548; COSMIC: COSV60121609;