rs374163604

chrX-153693925-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP3 BP4 BP6_Very_Strong BS2

The NM_005629.4(SLC6A8):c.1162G>A(p.Ala388Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,166,022 control chromosomes in the GnomAD database, including 1 homozygotes. There are 161 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A388A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.00048 (1 hom. 153 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 9.85

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 -10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005629.4
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.40768263).
• BP6: Variant X-153693925-G-A is Benign according to our data. Variant chrX-153693925-G-A is described in ClinVar as [Benign]. Clinvar id is 436771.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-153693925-G-A is described in Lovd as [Benign]. Variant chrX-153693925-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1162G>A	p.Ala388Thr	missense_variant	8/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1132G>A	p.Ala378Thr	missense_variant	8/13
SLC6A8	NM_001142806.1	c.817G>A	p.Ala273Thr	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1162G>A	p.Ala388Thr	missense_variant	8/13	1	NM_005629.4	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 34 AN: 112742 Hom.: 0 Cov.: 24 AF XY: 0.000229 AC XY: 8 AN XY: 34878

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000642

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000432

Gnomad OTH AF: 0.000657

GnomAD3 exomes AF: 0.000330 AC: 39 AN: 118182 Hom.: 0 AF XY: 0.000321 AC XY: 13 AN XY: 40552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000692

Gnomad FIN exome AF: 0.00109

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000479 AC: 504 AN: 1053227 Hom.: 1 Cov.: 32 AF XY: 0.000446 AC XY: 153 AN XY: 342745

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000353

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000200

Gnomad4 FIN exome AF: 0.000911

Gnomad4 NFE exome AF: 0.000561

Gnomad4 OTH exome AF: 0.000203

GnomAD4 genome AF: 0.000301 AC: 34 AN: 112795 Hom.: 0 Cov.: 24 AF XY: 0.000229 AC XY: 8 AN XY: 34941

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000278

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000642

Gnomad4 NFE AF: 0.000432

Gnomad4 OTH AF: 0.000649

Alfa AF: 0.000715 Hom.: 6

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000453 AC: 3

ExAC AF: 0.0000943 AC: 10

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Feb 23, 2023	The NM_005629.4(SLC6A8):c.1162G>A (p.Ala388Thr) variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Alanine at amino acid 338 (p.Ala338Thr). There is a ClinVar entry for this variant (Variation ID:436771). This variant is found with an allele frequency of 0.003854 in gnomADv2.1.1 with 17 hemizygotes present in that population database. Given the presence of >10 hemizygotes in gnomADv2.1.1 and an allele frequency >0.002, the stand alone benign criteria BA1 is applicable for this variant. In summary, this variant meets the criteria to be classified as Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0; ; classification approved Feb 23, 2023): BA1 -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SLC6A8: PP2, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as a non-pathogenic variant in a male with intellectual disability and normal creatine uptake in cultured skin fibroblasts (Betsalel et al, 2011).; This variant is associated with the following publications: (PMID: 28758966, 22281021, 26684475, 20717164, 25861866) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 22, 2016

- -

Creatine deficiency syndrome 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2019

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
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.020	D;T
Polyphen		0.97	D;.
Vest4		0.61
MVP		0.93
MPC		2.3
ClinPred		0.31	T
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.83
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs374163604; hg19: chrX-152959380;