rs144556614

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_139319.3(SLC17A8):c.705G>A(p.Met235Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

SLC17A8
NM_139319.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 10.0

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A8	NM_139319.3 link	c.705G>A	p.Met235Ile	missense_variant	Exon 6 of 12	ENST00000323346.10	NP_647480.1
SLC17A8	NM_001145288.2 link	c.705G>A	p.Met235Ile	missense_variant	Exon 6 of 11		NP_001138760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A8	ENST00000323346.10 link	c.705G>A	p.Met235Ile	missense_variant	Exon 6 of 12	1	NM_139319.3	ENSP00000316909.4
SLC17A8	ENST00000392989.3 link	c.705G>A	p.Met235Ile	missense_variant	Exon 6 of 11	1		ENSP00000376715.3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251246

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 26, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Met235Ile varia nt in SLC17A8 has not been previously reported in individuals with hearing loss, but has been identified in 0.02% (1/4406) of African American chromosomes by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs144 556614). In addition, this variant did not segregate in this individual's siblin g who also has a hearing loss. Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Met235I le variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the arguments d escribed above, we would lean towards a more likely benign role.

not provided

Uncertain:1

Jan 25, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Benign

-0.34

MutationAssessor

Benign

2.0

M;M

PhyloP100

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.025

D;D

Sift4G

Benign

0.075

T;T

Vest4

0.78

ClinPred

0.95

GERP RS

5.5

Varity_R

0.61

gMVP

0.89

Mutation Taster

=9/91

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over