Genetic Variant NM_005629.4:c.1208C>T (chrX-153693971-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_005629.4(SLC6A8):c.1208C>T(p.Ala403Val) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.80

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

creatine transporter deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SLC6A8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005629.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant X-153693971-C-T is Pathogenic according to our data. Variant chrX-153693971-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523485.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1208C>T	p.Ala403Val	missense_variant	Exon 8 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1178C>T	p.Ala393Val	missense_variant	Exon 8 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.863C>T	p.Ala288Val	missense_variant	Exon 8 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.1208C>T	p.Ala403Val	missense_variant	Exon 8 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1064367

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

345973

African (AFR)

AF:

0.00

AC:

AN:

25691

American (AMR)

AF:

0.00

AC:

AN:

30100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18818

East Asian (EAS)

AF:

0.00

AC:

AN:

28532

South Asian (SAS)

AF:

0.00

AC:

AN:

50827

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3103

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

824544

Other (OTH)

AF:

0.00

AC:

AN:

44788

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Seizure;C0239234:Low-set ears;C0424503:Abnormal facial shape;C3714756:Intellectual disability

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.9

H;.

PhyloP100

7.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.74

P;.

Vest4

0.78

MutPred

0.72

Loss of glycosylation at P400 (P = 0.2724);.;

MVP

0.99

MPC

2.4

ClinPred

1.0

GERP RS

4.8

Varity_R

0.94

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over