NM_003042.4:c.152T>A

Variant names:

• chr3-11017363-T-A
• rs1553687887
• NM_003042.4:c.152T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 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:2 B:1
• Conservation: PhyloP100: 6.09
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 12 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 475474.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.152T>A	p.Phe51Tyr	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.152T>A	p.Phe51Tyr	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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Uncertain:1 Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 12, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PP2 -

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;.;.;.
PhyloP100		6.1
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
PromoterAI		0.011	Neutral
Varity_R		0.39
gMVP		0.65
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs1553687887; hg19: chr3-11059049;