12-100401921-A-G

Variant names:

• chr12-100401921-A-G
• rs11568544
• NM_139319.3:c.763+58A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139319.3(SLC17A8):​c.763+58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,366,948 control chromosomes in the GnomAD database, including 80,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7343 hom., cov: 31)
  • Exomes 𝑓: 0.34 (73525 hom.)
• Consequence: SLC17A8 NM_139319.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.608
• 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

LOC124903108 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-100401921-A-G is Benign according to our data. Variant chr12-100401921-A-G is described in ClinVar as Benign. ClinVar VariationId is 1247732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	NM_139319.3	MANE Select	c.763+58A>G		intron	N/A	NP_647480.1
	SLC17A8	NM_001145288.2		c.763+58A>G		intron	N/A	NP_001138760.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A8	ENST00000323346.10	TSL:1 MANE Select	c.763+58A>G		intron	N/A	ENSP00000316909.4
	SLC17A8	ENST00000392989.3	TSL:1	c.763+58A>G		intron	N/A	ENSP00000376715.3
	SLC17A8	ENST00000874772.1		c.763+58A>G		intron	N/A	ENSP00000544831.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44471 AN: 151916 Hom.: 7344 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.314

GnomAD4 exome AF: 0.336 AC: 408170 AN: 1214914 Hom.: 73525 AF XY: 0.335 AC XY: 206679 AN XY: 616604

African (AFR) AF: 0.164 AC: 4730 AN: 28804

American (AMR) AF: 0.198 AC: 8805 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 9553 AN: 24496

East Asian (EAS) AF: 0.0564 AC: 2178 AN: 38608

South Asian (SAS) AF: 0.246 AC: 19883 AN: 80944

European-Finnish (FIN) AF: 0.436 AC: 23127 AN: 52992

Middle Eastern (MID) AF: 0.321 AC: 1702 AN: 5304

European-Non Finnish (NFE) AF: 0.362 AC: 321396 AN: 886988

Other (OTH) AF: 0.321 AC: 16796 AN: 52364

GnomAD4 genome AF: 0.293 AC: 44485 AN: 152034 Hom.: 7343 Cov.: 31 AF XY: 0.291 AC XY: 21667 AN XY: 74332

African (AFR) AF: 0.172 AC: 7121 AN: 41486

American (AMR) AF: 0.264 AC: 4029 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1375 AN: 3470

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5176

South Asian (SAS) AF: 0.236 AC: 1138 AN: 4816

European-Finnish (FIN) AF: 0.434 AC: 4584 AN: 10562

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24944 AN: 67956

Other (OTH) AF: 0.314 AC: 663 AN: 2112

Alfa AF: 0.280 Hom.: 1684

Bravo AF: 0.274

Asia WGS AF: 0.155 AC: 540 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		0.61
Mutation Taster		=100/0	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: rs11568544; hg19: chr12-100795699; COSMIC: COSV60124814; COSMIC: COSV60124814;