chr3-11017248-A-T

Variant names:

• chr3-11017248-A-T
• rs1553687808
• NM_003042.4:c.37A>T

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>T​(p.Ile13Phe) 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. Variant has been reported in ClinVar 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 the SLC6A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 4.1766 (above the threshold of 3.09). Trascript score misZ: 4.9229 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26386455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.37A>T	p.Ile13Phe	missense_variant	Exon 3 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.37A>T	p.Ile13Phe	missense_variant	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4

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

Epilepsy with myoclonic atonic seizures Uncertain:1

Oct 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant has not been reported in the literature in individuals with SLC6A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 13 of the SLC6A1 protein (p.Ile13Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.
Eigen	Benign	0.087
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.21	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.26	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	-0.68	T
MutationAssessor	Benign	0.81	L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;.;L;L;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.55	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.099	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.10	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.66	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;.;P;.;P;P;.;.;.
Vest4		0.38
MutPred		0.16		Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);Loss of glycosylation at T15 (P = 0.0777);
MVP		0.67
MPC		1.7
ClinPred		0.61	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.51

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;