3-11017248-A-G

Position:

• chr3-11017248-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003042.4(SLC6A1):​c.37A>G​(p.Ile13Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I13F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.09877223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.37A>G	p.Ile13Val	missense_variant	3/16	ENST00000287766.10
SLC6A1-AS1	NR_046647.1	n.105+1872T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.37A>G	p.Ile13Val	missense_variant	3/16	1	NM_003042.4	P1
SLC6A1-AS1	ENST00000414969.2	n.105+1872T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic-atonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A1 protein function. ClinVar contains an entry for this variant (Variation ID: 542197). This variant has not been reported in the literature in individuals affected with SLC6A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the SLC6A1 protein (p.Ile13Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.18	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.099	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	-0.94	T
MutationAssessor	Benign	0.26	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;.;N;N;.;.;.
MutationTaster	Benign	0.56	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.35	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.81	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;.;B;B;.;.;.
Vest4		0.076
MutPred		0.16		Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);Gain of glycosylation at S18 (P = 0.1103);
MVP		0.46
MPC		0.86
ClinPred		0.31	T
GERP RS		4.4
Varity_R		0.087
gMVP		0.30

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: rs1553687808; hg19: chr3-11058934;