rs143916832

Variant names:

• chrX-153694445-C-G
• rs143916832
• NM_005629.4:c.1494C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005629.4(SLC6A8):​c.1494C>G​(p.Tyr498*) 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
• Publications: 7 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1494C>G	p.Tyr498*	stop_gained, splice_region_variant	Exon 10 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1464C>G	p.Tyr488*	stop_gained, splice_region_variant	Exon 10 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1149C>G	p.Tyr383*	stop_gained, splice_region_variant	Exon 10 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1494C>G	p.Tyr498*	stop_gained, splice_region_variant	Exon 10 of 13	1	NM_005629.4	ENSP00000253122.5

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

Aug 20, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.5
Vest4		0.97
GERP RS		-0.93
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs143916832; hg19: chrX-152959900;