3-11017224-G-A

Position:

chr3-11017224-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_003042.4(SLC6A1):c.13G>A(p.Gly5Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.72

Variant links:

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 links:

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

SLC6A1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A1. . Gene score misZ 4.1766 (greater than the threshold 3.09). Trascript score misZ 4.9229 (greater than threshold 3.09). GenCC has associacion of gene with myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.

BP4

Computational evidence support a benign effect (MetaRNN=0.109599024).

BP6

Variant 3-11017224-G-A is Benign according to our data. Variant chr3-11017224-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2054325.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4 linkuse as main transcript	c.13G>A	p.Gly5Ser	missense_variant	3/16	ENST00000287766.10
SLC6A1-AS1	NR_046647.1 linkuse as main transcript	n.105+1896C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10 linkuse as main transcript	c.13G>A	p.Gly5Ser	missense_variant	3/16	1	NM_003042.4	P1
SLC6A1-AS1	ENST00000414969.2 linkuse as main transcript	n.105+1896C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250678

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000106

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myoclonic-atonic epilepsy

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2022	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.13G>A (p.G5S) alteration is located in exon 3 (coding exon 1) of the SLC6A1 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the glycine (G) at amino acid position 5 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.25

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;.;N;N;.;.;.

MutationTaster

Benign

0.71

D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.48

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.25

Sift

Benign

0.20

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.14

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.0090

B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;.;B;B;.;.;.

Vest4

0.16

MutPred

0.13

Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);Gain of phosphorylation at G5 (P = 0.049);

MVP

0.87

MPC

1.0

ClinPred

0.074

GERP RS

2.5

Varity_R

0.036

gMVP

0.73

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

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