rs1553692346

Positions:

• chr3-11036890-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_003042.4(SLC6A1):​c.1724A>T​(p.Glu575Val) 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E575K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.88

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]

ACMG classification

Verdict is Likely_benign. 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=0.16347033).
• BP6: Variant 3-11036890-A-T is Benign according to our data. Variant chr3-11036890-A-T is described in ClinVar as [Benign]. Clinvar id is 542199.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.1724A>T	p.Glu575Val	missense_variant	16/16	ENST00000287766.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1724A>T	p.Glu575Val	missense_variant	16/16	1	NM_003042.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic-atonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0048	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;T;.;.;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;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	-0.89	T
MutationAssessor	Benign	0.81	L;L;L;L;L;.;L;.;L;L;L;L;.;L;L;L;.;L;L;L;.;L;L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.16	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.25	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;B;B;B;B;.;B;.;B;B;B;B;.;B;B;B;.;B;B;B;.;B;B;B;.
Vest4		0.33
MutPred		0.39		Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;Loss of disorder (P = 0.0082);.;Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;
MVP		0.70
MPC		1.2
ClinPred		0.55	D
GERP RS		4.4
Varity_R		0.16
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1553692346; hg19: chr3-11078576;