rs34299874

chr3-11020276-A-Gchr3-11020276-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003042.4(SLC6A1):c.535A>G(p.Met179Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,454 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M179L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0083 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (13 hom.)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0710

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC6A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040431023).
• BP6: Variant 3-11020276-A-G is Benign according to our data. Variant chr3-11020276-A-G is described in ClinVar as [Benign]. Clinvar id is 475486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00833 (1269/152322) while in subpopulation AFR AF= 0.0287 (1193/41576). AF 95% confidence interval is 0.0273. There are 21 homozygotes in gnomad4. There are 636 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1266 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.535A>G	p.Met179Val	missense_variant	6/16	ENST00000287766.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.535A>G	p.Met179Val	missense_variant	6/16	1	NM_003042.4	P1

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152204 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00215 AC: 537 AN: 250100 Hom.: 6 AF XY: 0.00158 AC XY: 214 AN XY: 135128

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000828 AC: 1210 AN: 1461132 Hom.: 13 Cov.: 30 AF XY: 0.000711 AC XY: 517 AN XY: 726754

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00833 AC: 1269 AN: 152322 Hom.: 21 Cov.: 33 AF XY: 0.00854 AC XY: 636 AN XY: 74488

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00190 Hom.: 6

Bravo AF: 0.00936

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00274 AC: 333

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Myoclonic-atonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	4.6
Dann	Benign	0.64
DEOGEN2	Benign	0.11	T;T;T;.;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.0034	T;T;T;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	-1.1	T
MutationAssessor	Benign	-0.070	N;N;N;.;N;N;.;N;.;N;N;N;N;.;N;N;N;.;N;N;N;.;N;N;N;.;.
MutationTaster	Benign	0.52	D;N
PrimateAI	Benign	0.21	T
Polyphen		0.0010	B;B;B;.;B;B;.;B;.;B;B;B;B;.;B;B;B;.;B;B;B;.;B;B;B;.;.
Vest4		0.092
MVP		0.49
MPC		1.0
ClinPred		0.00032	T
GERP RS		-5.8
Varity_R		0.045
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: rs34299874; hg19: chr3-11061962;