Genetic Variant SLC17A8:c.355-3860A>G (chr12-100387141-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_139319.3(SLC17A8):c.355-3860A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 152,132 control chromosomes in the GnomAD database, including 42,042 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.74 ( 42042 hom., cov: 32)

Consequence

SLC17A8
NM_139319.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.248

Publications

4 publications found

Variant links:

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

SLC17A8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A8	NM_139319.3 link	c.355-3860A>G		intron_variant	Intron 2 of 11	ENST00000323346.10	NP_647480.1	Q8NDX2-1
SLC17A8	NM_001145288.2 link	c.355-3860A>G		intron_variant	Intron 2 of 10		NP_001138760.1	Q8NDX2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A8	ENST00000323346.10 link	c.355-3860A>G		intron_variant	Intron 2 of 11	1	NM_139319.3	ENSP00000316909.4		Q8NDX2-1
SLC17A8	ENST00000392989.3 link	c.355-3860A>G		intron_variant	Intron 2 of 10	1		ENSP00000376715.3		Q8NDX2-2

Frequencies

GnomAD3 genomes

AF:

0.740

AC:

112460

AN:

152014

Hom.:

42017

Cov.:

show subpopulations

Gnomad AFR

AF:

0.702

Gnomad AMI

AF:

0.654

Gnomad AMR

AF:

0.830

Gnomad ASJ

AF:

0.818

Gnomad EAS

AF:

0.952

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.697

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.724

Gnomad OTH

AF:

0.742

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.740

AC:

112533

AN:

152132

Hom.:

42042

Cov.:

AF XY:

0.742

AC XY:

55150

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.701

AC:

29110

AN:

41498

American (AMR)

AF:

0.830

AC:

12694

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.818

AC:

2835

AN:

3466

East Asian (EAS)

AF:

0.952

AC:

4932

AN:

5178

South Asian (SAS)

AF:

0.830

AC:

4002

AN:

4824

European-Finnish (FIN)

AF:

0.697

AC:

7369

AN:

10572

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.724

AC:

49215

AN:

67992

Other (OTH)

AF:

0.744

AC:

1566

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1510

3020

4529

6039

7549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.738

Hom.:

131311

Bravo

AF:

0.750

Asia WGS

AF:

0.854

AC:

2971

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.89

(source)

DANN

Benign

0.72

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over