rs782703394

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005629.4(SLC6A8):c.1570T>A(p.Ser524Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,156,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.00014 ( 0 hom. 47 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.169

Variant links:

Genes affected

SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17356688).

BP6

Variant X-153694607-T-A is Benign according to our data. Variant chrX-153694607-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410223.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC6A8	NM_005629.4 linkuse as main transcript	c.1570T>A	p.Ser524Thr	missense_variant	11/13	ENST00000253122.10
SLC6A8	NM_001142805.2 linkuse as main transcript	c.1540T>A	p.Ser514Thr	missense_variant	11/13
SLC6A8	NM_001142806.1 linkuse as main transcript	c.1225T>A	p.Ser409Thr	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.1570T>A	p.Ser524Thr	missense_variant	11/13	1	NM_005629.4	P1	P48029-1
SLC6A8	ENST00000430077.6 linkuse as main transcript	c.1225T>A	p.Ser409Thr	missense_variant	11/13	2			P48029-4
SLC6A8	ENST00000485324.1 linkuse as main transcript	n.1877T>A		non_coding_transcript_exon_variant	4/6	2
SLC6A8	ENST00000413787.1 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000974

AC:

AN:

102673

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

28417

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000102

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:

0.000179

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000274

AC:

AN:

182654

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

146

AN:

1053851

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

340453

show subpopulations

Gnomad4 AFR exome

AF:

0.0000399

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.0000924

GnomAD4 genome

AF:

0.0000974

AC:

AN:

102673

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

28417

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000102

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000179

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	SLC6A8: BP4 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2019

The p.S524T variant (also known as c.1570T>A), located in coding exon 11 of the SLC6A8 gene, results from a T to A substitution at nucleotide position 1570. The serine at codon 524 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Creatine transporter deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Benign

0.89

DEOGEN2

Benign

0.096

T;.

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.19

Sift

Benign

0.51

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.061

B;.

Vest4

0.35

MutPred

0.53

Loss of ubiquitination at K520 (P = 0.1166);.;

MVP

0.61

MPC

0.26

ClinPred

0.043

GERP RS

4.9

Varity_R

0.22

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over