NM_003042.4:c.1191+9G>A

Variant names:

• chr3-11028856-G-A
• rs761322748
• NM_003042.4:c.1191+9G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003042.4(SLC6A1):​c.1191+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,571,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SLC6A1 NM_003042.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.61
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 3-11028856-G-A is Benign according to our data. Variant chr3-11028856-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 542209.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000357 (54/151272) while in subpopulation AFR AF = 0.00121 (50/41220). AF 95% confidence interval is 0.000945. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 54 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.1191+9G>A		intron	N/A	NP_003033.3
	SLC6A1	NM_001348250.2		c.1191+9G>A		intron	N/A	NP_001335179.1
	SLC6A1	NM_001348251.2		c.831+9G>A		intron	N/A	NP_001335180.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.1191+9G>A		intron	N/A	ENSP00000287766.4
	SLC6A1	ENST00000645598.1		n.1032G>A		non_coding_transcript_exon	Exon 9 of 9
	SLC6A1	ENST00000698198.1		c.1263+9G>A		intron	N/A	ENSP00000513602.1

Frequencies

GnomAD3 genomes AF: 0.000344 AC: 52 AN: 151154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000102 AC: 24 AN: 234778 AF XY: 0.000110

Gnomad AFR exome AF: 0.000896

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000535 AC: 76 AN: 1420716 Hom.: 0 Cov.: 26 AF XY: 0.0000578 AC XY: 41 AN XY: 709088

African (AFR) AF: 0.000866 AC: 28 AN: 32314

American (AMR) AF: 0.000157 AC: 7 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39416

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53022

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5556

European-Non Finnish (NFE) AF: 0.0000288 AC: 31 AN: 1076120

Other (OTH) AF: 0.000102 AC: 6 AN: 58940

GnomAD4 genome AF: 0.000357 AC: 54 AN: 151272 Hom.: 0 Cov.: 31 AF XY: 0.000284 AC XY: 21 AN XY: 73874

African (AFR) AF: 0.00121 AC: 50 AN: 41220

American (AMR) AF: 0.000198 AC: 3 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67772

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000457

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy with myoclonic atonic seizures (1)
-	-	1	SLC6A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.083
DANN	Benign	0.51
PhyloP100		-3.6

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: rs761322748; hg19: chr3-11070542; COSMIC: COSV55115302; COSMIC: COSV55115302;