rs748779390

chr3-11020234-G-Achr3-11020234-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_003042.4(SLC6A1):c.493G>A(p.Asp165Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.65

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 -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC6A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15709153).
• BP6: Variant 3-11020234-G-A is Benign according to our data. Variant chr3-11020234-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475484.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.493G>A	p.Asp165Asn	missense_variant	6/16	ENST00000287766.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.493G>A	p.Asp165Asn	missense_variant	6/16	1	NM_003042.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250356 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461114 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726794

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myoclonic-atonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2017

In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is present in population databases (rs748779390, ExAC 0.002%) but has not been reported in the literature in individuals with a SLC6A1-related disease. This sequence change replaces aspartic acid with asparagine at codon 165 of the SLC6A1 protein (p.Asp165Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

SLC6A1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.099	T;T;T;.;T;T;T;T;T;T;T;T;T;T;.;T;T;T;.;T;T;T;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.012	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
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.48	N;N;N;.;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;N;N;N;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.39	T
Polyphen		0.014	B;B;B;.;B;B;B;B;B;B;B;B;B;B;.;B;B;B;.;B;B;B;.;.
Vest4		0.12
MutPred		0.45		Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);.;Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);.;Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);.;Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);Gain of catalytic residue at D165 (P = 0.0504);
MVP		0.85
MPC		1.0
ClinPred		0.42	T
GERP RS		3.3
Varity_R		0.069
gMVP		0.50

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: rs748779390; hg19: chr3-11061920; COSMIC: COSV99822332; COSMIC: COSV99822332;