rs748779390

Variant names:

• chr3-11020234-G-A
• rs748779390
• NM_003042.4:c.493G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-11020234-G-A
• chr3-11020234-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

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. 17/22 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
• Publications: 3 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 Gene-Disease associations (from GenCC):

• epilepsy with myoclonic atonic seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_003042.4
• 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 VariationId is 475484.
• BS2: High AC in GnomAdExome4 at 7 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.493G>A	p.Asp165Asn	missense_variant	Exon 6 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.493G>A	p.Asp165Asn	missense_variant	Exon 6 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250356 AF XY: 0.0000148

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Epilepsy with myoclonic atonic seizures Uncertain:1

Apr 06, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Uncertain	0.92	.;.;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;D;D;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;.;.
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.28	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.98	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	.;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
Mutation Taster		=82/18	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: rs748779390; hg19: chr3-11061920; COSMIC: COSV99822332; COSMIC: COSV99822332;