3-10874970-G-T

Variant names:

• chr3-10874970-G-T
• rs138109295
• NM_014229.3:c.766G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_014229.3(SLC6A11):​c.766G>T​(p.Val256Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,611,220 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V256M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SLC6A11 NM_014229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32
• Publications: 2 publications found

Genes affected

SLC6A11 (HGNC:11044): (solute carrier family 6 member 11) The protein encoded by this gene is a sodium-dependent transporter that uptakes gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, which ends the GABA neurotransmission. Defects in this gene may result in epilepsy, behavioral problems, or intellectual problems. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3439812).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014229.3. 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
	SLC6A11	NM_014229.3	MANE Select	c.766G>T	p.Val256Leu	missense	Exon 6 of 14	NP_055044.1	P48066-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A11	ENST00000254488.7	TSL:1 MANE Select	c.766G>T	p.Val256Leu	missense	Exon 6 of 14	ENSP00000254488.2	P48066-1
	SLC6A11	ENST00000861594.1		c.490G>T	p.Val164Leu	missense	Exon 4 of 12	ENSP00000531653.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 249378 AF XY: 0.000148

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1459064 Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 119 AN XY: 725806

African (AFR) AF: 0.0000599 AC: 2 AN: 33386

American (AMR) AF: 0.0000225 AC: 1 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85770

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000212 AC: 235 AN: 1110416

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.0000724 AC: 3 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.37	N
REVEL	Uncertain	0.32
Sift	Benign	0.047	D
Sift4G	Benign	0.091	T
Polyphen		0.053	B
Vest4		0.50
MutPred		0.53		Loss of methylation at K252 (P = 0.0744)
MVP		0.75
MPC		1.1
ClinPred		0.061	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.75
Mutation Taster		=60/40	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: rs138109295; hg19: chr3-10916655;