rs150207268

chrX-153695071-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005629.4(SLC6A8):c.1768-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,198,729 control chromosomes in the GnomAD database, including 18 homozygotes. There are 2,195 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (0 hom., 144 hem., cov: 23)
  • Exomes 𝑓: 0.0060 (18 hom. 2051 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.07024
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.07

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-153695071-C-T is Benign according to our data. Variant chrX-153695071-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153695071-C-T is described in Lovd as [Benign]. Variant chrX-153695071-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00435 (490/112720) while in subpopulation AMR AF= 0.0078 (84/10773). AF 95% confidence interval is 0.00645. There are 0 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 144 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1768-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000253122.10
SLC6A8	NM_001142805.2	c.1738-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC6A8	NM_001142806.1	c.1423-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1768-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005629.4	P1
SLC6A8	ENST00000430077.6	c.1423-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
SLC6A8	ENST00000485324.1	n.2075-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 490 AN: 112668 Hom.: 0 Cov.: 23 AF XY: 0.00414 AC XY: 144 AN XY: 34814

Gnomad AFR AF: 0.000516

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.00781

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000725

Gnomad FIN AF: 0.00112

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00265

GnomAD3 exomes AF: 0.00445 AC: 709 AN: 159238 Hom.: 2 AF XY: 0.00404 AC XY: 202 AN XY: 50018

Gnomad AFR exome AF: 0.000445

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00160

Gnomad NFE exome AF: 0.00701

Gnomad OTH exome AF: 0.00797

GnomAD4 exome AF: 0.00604 AC: 6559 AN: 1086009 Hom.: 18 Cov.: 31 AF XY: 0.00579 AC XY: 2051 AN XY: 354315

Gnomad4 AFR exome AF: 0.000496

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000804

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00688

Gnomad4 OTH exome AF: 0.00582

GnomAD4 genome AF: 0.00435 AC: 490 AN: 112720 Hom.: 0 Cov.: 23 AF XY: 0.00413 AC XY: 144 AN XY: 34876

Gnomad4 AFR AF: 0.000515

Gnomad4 AMR AF: 0.00780

Gnomad4 ASJ AF: 0.0139

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000727

Gnomad4 FIN AF: 0.00112

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00261

Alfa AF: 0.00698 Hom.: 56

Bravo AF: 0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Creatine transporter deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 18, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.7% (84/10760) including 39 hemizygotes (https://gnomad.broadinstitute.org/variant/X-153695071-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:212213). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Creatine deficiency syndrome 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 20, 2019

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SLC6A8-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	15
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.070
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs150207268; hg19: chrX-152960526;