rs183069336

chr3-11017349-G-Achr3-11017349-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003042.4(SLC6A1):c.138G>A(p.Thr46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,216 control chromosomes in the GnomAD database, including 123 homozygotes. 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. T46T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (106 hom.)
• Consequence: SLC6A1 NM_003042.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.74

Genes affected

SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

SLC6A1-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-11017349-G-A is Benign according to our data. Variant chr3-11017349-G-A is described in ClinVar as [Benign]. Clinvar id is 475471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.138G>A	p.Thr46=	synonymous_variant	3/16	ENST00000287766.10
SLC6A1-AS1	NR_046647.1	n.105+1771C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.138G>A	p.Thr46=	synonymous_variant	3/16	1	NM_003042.4	P1
SLC6A1-AS1	ENST00000414969.2	n.105+1771C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 742 AN: 152208 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00908 AC: 2282 AN: 251458 Hom.: 76 AF XY: 0.00708 AC XY: 962 AN XY: 135920

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0130

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00235 AC: 3440 AN: 1461890 Hom.: 106 Cov.: 31 AF XY: 0.00206 AC XY: 1495 AN XY: 727246

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.0541

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152326 Hom.: 17 Cov.: 32 AF XY: 0.00562 AC XY: 419 AN XY: 74490

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.00795

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 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. -

Myoclonic-atonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

SLC6A1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 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	-0.51
Cadd	Benign	4.9
Dann	Benign	0.88

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: rs183069336; hg19: chr3-11059035; COSMIC: COSV55117002; COSMIC: COSV55117002;