3-10819745-A-T

Position:

• chr3-10819745-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014229.3(SLC6A11):​c.425A>T​(p.His142Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A11 NM_014229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2004202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A11	NM_014229.3	c.425A>T	p.His142Leu	missense_variant	3/14	ENST00000254488.7	NP_055044.1
SLC6A11	NM_001317406.3	c.425A>T	p.His142Leu	missense_variant	3/4		NP_001304335.1
SLC6A11	XM_011534033.3	c.425A>T	p.His142Leu	missense_variant	3/9		XP_011532335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A11	ENST00000254488.7	c.425A>T	p.His142Leu	missense_variant	3/14	1	NM_014229.3	ENSP00000254488.2
SLC6A11	ENST00000454147.1	c.425A>T	p.His142Leu	missense_variant	3/4	1		ENSP00000404120.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.425A>T (p.H142L) alteration is located in exon 3 (coding exon 3) of the SLC6A11 gene. This alteration results from a A to T substitution at nucleotide position 425, causing the histidine (H) at amino acid position 142 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.086	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.9	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.23
Sift	Benign	0.85	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;.
Vest4		0.48
MutPred		0.61		Gain of catalytic residue at H142 (P = 0.0312);Gain of catalytic residue at H142 (P = 0.0312);
MVP		0.68
MPC		1.3
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.31
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs891572485; hg19: chr3-10861430;