rs1553687887

Positions:

• chr3-11017363-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F51L) has been classified as Uncertain significance.

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 7 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC6A1
• 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: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.152T>A	p.Phe51Tyr	missense_variant	3/16	ENST00000287766.10
SLC6A1-AS1	NR_046647.1	n.105+1757A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.152T>A	p.Phe51Tyr	missense_variant	3/16	1	NM_003042.4	P1
SLC6A1-AS1	ENST00000414969.2	n.105+1757A>T		intron_variant, non_coding_transcript_variant		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

Invitae

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
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;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
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;