rs33948309

Variant names:

• chr3-11025514-G-A
• rs33948309
• NM_003042.4:c.780G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003042.4(SLC6A1):​c.780G>A​(p.Thr260Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,052 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (98 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (57 hom.)
• Consequence: SLC6A1 NM_003042.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.995
• Publications: 2 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina, G2P
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-11025514-G-A is Benign according to our data. Variant chr3-11025514-G-A is described in ClinVar as Benign. ClinVar VariationId is 475490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.995 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003042.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.780G>A	p.Thr260Thr	synonymous	Exon 8 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.780G>A	p.Thr260Thr	synonymous	Exon 8 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.420G>A	p.Thr140Thr	synonymous	Exon 8 of 16	NP_001335180.1	A0A2R8Y4I3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.780G>A	p.Thr260Thr	synonymous	Exon 8 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.852G>A	p.Thr284Thr	synonymous	Exon 6 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.780G>A	p.Thr260Thr	synonymous	Exon 6 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2877 AN: 152106 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00481 AC: 1208 AN: 251360 AF XY: 0.00343

Gnomad AFR exome AF: 0.0618

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00190 AC: 2773 AN: 1461828 Hom.: 57 Cov.: 31 AF XY: 0.00165 AC XY: 1198 AN XY: 727218

African (AFR) AF: 0.0617 AC: 2064 AN: 33478

American (AMR) AF: 0.00494 AC: 221 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000160 AC: 178 AN: 1111966

Other (OTH) AF: 0.00470 AC: 284 AN: 60394

GnomAD4 genome AF: 0.0189 AC: 2880 AN: 152224 Hom.: 98 Cov.: 32 AF XY: 0.0182 AC XY: 1351 AN XY: 74428

African (AFR) AF: 0.0654 AC: 2717 AN: 41516

American (AMR) AF: 0.00725 AC: 111 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68018

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0163 Hom.: 53

Bravo AF: 0.0218

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Epilepsy with myoclonic atonic seizures (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.7
DANN	Benign	0.70
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs33948309; hg19: chr3-11067200;