rs112095333

chr3-11029272-C-A

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.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. 14/20 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

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=0.006750524).
• BP6: Variant 3-11029272-C-A is Benign according to our data. Variant chr3-11029272-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 377065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-11029272-C-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 364 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.1243C>A	p.Leu415Ile	missense_variant	12/16	ENST00000287766.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1243C>A	p.Leu415Ile	missense_variant	12/16	1	NM_003042.4	P1

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

GnomAD3 exomes AF: 0.00251 AC: 622 AN: 247704 Hom.: 1 AF XY: 0.00253 AC XY: 338 AN XY: 133780

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 SAS 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

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00341

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

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00375 Hom.: 5

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

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SLC6A1: BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2017

This alteration is classified as likely 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

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.096	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0068	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	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;L;L;.;L;.;L;L;L;L;.;L;L;L;.;L;L;L;.;L;L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
Polyphen		0.0020	B;B;B;B;B;.;B;.;B;B;B;B;.;B;B;B;.;B;B;B;.;B;B;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

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: rs112095333; hg19: chr3-11070958; COSMIC: COSV105157147; COSMIC: COSV105157147;