rs150207268

Positions:

chrX-153695071-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

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. 3/3 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

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 -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. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 144 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
SLC6A8	NM_005629.4 linkuse as main transcript	c.1768-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 linkuse as main transcript	c.1738-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001136277.1
SLC6A8	NM_001142806.1 linkuse as main transcript	c.1423-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.1768-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_005629.4	ENSP00000253122	P1	P48029-1
SLC6A8	ENST00000430077.6 linkuse as main transcript	c.1423-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2		ENSP00000403041		P48029-4
SLC6A8	ENST00000485324.1 linkuse as main transcript	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.:

Cov.:

AF XY:

0.00414

AC XY:

144

AN XY:

34814

show subpopulations

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.:

AF XY:

0.00404

AC XY:

202

AN XY:

50018

show subpopulations

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.:

Cov.:

AF XY:

0.00579

AC XY:

2051

AN XY:

354315

show subpopulations

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.:

Cov.:

AF XY:

0.00413

AC XY:

144

AN XY:

34876

show subpopulations

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.:

Bravo

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Creatine transporter deficiency

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Creatine deficiency syndrome 1

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 20, 2019

- -

SLC6A8-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

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

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