3-11025835-C-T

Variant names:

• chr3-11025835-C-T
• rs35450949
• NM_003042.4:c.912C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003042.4(SLC6A1):​c.912C>T​(p.Ile304Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,613,828 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I304I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: SLC6A1 NM_003042.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.534
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-11025835-C-T is Benign according to our data. Variant chr3-11025835-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.534 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00178 (271/152220) while in subpopulation AFR AF = 0.00568 (236/41528). AF 95% confidence interval is 0.00509. There are 1 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 271 AD,Unknown gene.

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.912C>T	p.Ile304Ile	synonymous	Exon 9 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.912C>T	p.Ile304Ile	synonymous	Exon 9 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.552C>T	p.Ile184Ile	synonymous	Exon 9 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.912C>T	p.Ile304Ile	synonymous	Exon 9 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.984C>T	p.Ile328Ile	synonymous	Exon 7 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.912C>T	p.Ile304Ile	synonymous	Exon 7 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00568

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000569 AC: 143 AN: 251456 AF XY: 0.000441

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000260 AC: 380 AN: 1461608 Hom.: 2 Cov.: 31 AF XY: 0.000226 AC XY: 164 AN XY: 727124

African (AFR) AF: 0.00678 AC: 227 AN: 33478

American (AMR) AF: 0.000850 AC: 38 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111780

Other (OTH) AF: 0.00103 AC: 62 AN: 60386

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74408

African (AFR) AF: 0.00568 AC: 236 AN: 41528

American (AMR) AF: 0.00170 AC: 26 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.000655 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Epilepsy with myoclonic atonic seizures (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	4.7
DANN	Benign	0.76
PhyloP100		-0.53
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35450949; hg19: chr3-11067521; COSMIC: COSV55113201; COSMIC: COSV55113201;