12-100393442-G-T

Variant names:

• chr12-100393442-G-T
• rs150737570
• NM_139319.3:c.547G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_139319.3(SLC17A8):​c.547G>T​(p.Gly183*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC17A8 NM_139319.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.547G>T	p.Gly183*	stop_gained	Exon 4 of 12	NP_647480.1	Q8NDX2-1
	SLC17A8	NM_001145288.2		c.547G>T	p.Gly183*	stop_gained	Exon 4 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.547G>T	p.Gly183*	stop_gained	Exon 4 of 12	ENSP00000316909.4	Q8NDX2-1
	SLC17A8	ENST00000392989.3	TSL:1	c.547G>T	p.Gly183*	stop_gained	Exon 4 of 11	ENSP00000376715.3	Q8NDX2-2
	SLC17A8	ENST00000874772.1		c.547G>T	p.Gly183*	stop_gained	Exon 5 of 13	ENSP00000544831.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.8
Vest4		0.92
GERP RS		4.4
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150737570; hg19: chr12-100787220; COSMIC: COSV100035839;