rs143916832

Positions:

• chrX-153694445-C-G
• chrX-153694445-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005629.4(SLC6A8):​c.1494C>G​(p.Tyr498Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y498Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC6A8 NM_005629.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0005540
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -2.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PP5: Variant X-153694445-C-G is Pathogenic according to our data. Variant chrX-153694445-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 827674.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153694445-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1494C>G	p.Tyr498Ter	stop_gained, splice_region_variant	10/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1464C>G	p.Tyr488Ter	stop_gained, splice_region_variant	10/13
SLC6A8	NM_001142806.1	c.1149C>G	p.Tyr383Ter	stop_gained, splice_region_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1494C>G	p.Tyr498Ter	stop_gained, splice_region_variant	10/13	1	NM_005629.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Creatine transporter deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St George's Genomics Service, St George's University Hospitals NHS FT

Aug 20, 2018

This variant was identified via whole exome and subsequently whole genome analysis of a family trio. In this family the variant has been shown to occur de novo and was not reported in any reviewed variant databases at the time of identification; however other pathogenic nonsense variants 3' to this variant have been reported. The consequence is predicted to be a truncated protein (stop gain) with loss of the 3' portion of the Sodium:neurotransmitter symporter, creatine (IPR002984) domain. Complete loss of a protein product or residual functionality of a truncated protein product has not been confirmed by further investigations. Variants in this X-linked gene have previously been associated with cerebral creatine deficiency syndrome (type 1) and matched phenotypically. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.43	N
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		-0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: -25

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

Publications

LitVar

Other links and lift over

dbSNP: rs143916832; hg19: chrX-152959900;