rs1553687887

Positions:

• chr3-11017363-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_003042.4(SLC6A1):​c.152T>A​(p.Phe51Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.09

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.
• BP6: Variant 3-11017363-T-A is Benign according to our data. Variant chr3-11017363-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475474.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.152T>A	p.Phe51Tyr	missense_variant	3/16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.152T>A	p.Phe51Tyr	missense_variant	3/16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myoclonic-astatic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Myoclonic-atonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;.;.;.
Eigen	Benign	-0.015
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;T;D;T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.039	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.018	B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.
Vest4		0.60
MutPred		0.59		Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);Gain of ubiquitination at K48 (P = 0.0872);
MVP		0.98
MPC		1.2
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.39
gMVP		0.65

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: rs1553687887; hg19: chr3-11059049;