rs112095333

Variant names:

• chr3-11029272-C-A
• rs112095333
• NM_003042.4:c.1243C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-11029272-C-A
• chr3-11029272-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003042.4(SLC6A1):​c.1243C>A​(p.Leu415Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,612,416 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L415F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (14 hom.)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.521
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006750524).
• BP6: Variant 3-11029272-C-A is Benign according to our data. Variant chr3-11029272-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00239 (364/152282) while in subpopulation NFE AF = 0.00422 (287/68008). AF 95% confidence interval is 0.00382. There are 2 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 364 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.1243C>A	p.Leu415Ile	missense	Exon 12 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.1243C>A	p.Leu415Ile	missense	Exon 12 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.883C>A	p.Leu295Ile	missense	Exon 12 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.1243C>A	p.Leu415Ile	missense	Exon 12 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.1315C>A	p.Leu439Ile	missense	Exon 10 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.1270C>A	p.Leu424Ile	missense	Exon 10 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00251 AC: 622 AN: 247704 AF XY: 0.00253

Gnomad AFR exome AF: 0.000503

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00400 AC: 5842 AN: 1460134 Hom.: 14 Cov.: 32 AF XY: 0.00395 AC XY: 2866 AN XY: 726168

African (AFR) AF: 0.000448 AC: 15 AN: 33462

American (AMR) AF: 0.00139 AC: 62 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85816

European-Finnish (FIN) AF: 0.00162 AC: 86 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00492 AC: 5470 AN: 1111200

Other (OTH) AF: 0.00341 AC: 206 AN: 60336

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74472

African (AFR) AF: 0.000794 AC: 33 AN: 41564

American (AMR) AF: 0.00183 AC: 28 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00366 Hom.: 7

Bravo AF: 0.00232

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Epilepsy with myoclonic atonic seizures (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.52
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.13
Sift	Benign	0.24	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.17
MVP		0.25
MPC		1.1
ClinPred		0.011	T
GERP RS		3.6
Varity_R		0.074
gMVP		0.49
Mutation Taster		=98/2	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: rs112095333; hg19: chr3-11070958; COSMIC: COSV105157147; COSMIC: COSV105157147;