NM_014229.3:c.110G>A

Variant names:

• chr3-10816375-G-A
• rs755212102
• NM_014229.3:c.110G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014229.3(SLC6A11):​c.110G>A​(p.Arg37His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,485,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R37L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SLC6A11 NM_014229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22091177).

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.110G>A	p.Arg37His	missense	Exon 1 of 14	NP_055044.1	P48066-1
	SLC6A11	NM_001317406.3		c.110G>A	p.Arg37His	missense	Exon 1 of 4	NP_001304335.1	P48066-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A11	ENST00000254488.7	TSL:1 MANE Select	c.110G>A	p.Arg37His	missense	Exon 1 of 14	ENSP00000254488.2	P48066-1
	SLC6A11	ENST00000454147.1	TSL:1	c.110G>A	p.Arg37His	missense	Exon 1 of 4	ENSP00000404120.1	P48066-2
	SLC6A11	ENST00000861594.1		c.110G>A	p.Arg37His	missense	Exon 1 of 12	ENSP00000531653.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151928 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1334024 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 658694

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000374 AC: 1 AN: 26730

American (AMR) AF: 0.00 AC: 0 AN: 25732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22618

East Asian (EAS) AF: 0.00 AC: 0 AN: 29728

South Asian (SAS) AF: 0.00 AC: 0 AN: 70370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4374

European-Non Finnish (NFE) AF: 9.51e-7 AC: 1 AN: 1051154

Other (OTH) AF: 0.00 AC: 0 AN: 54612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151928 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74202

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15244

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67942

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.0040	B
Vest4		0.12
MVP		0.58
MPC		0.78
ClinPred		0.24	T
GERP RS		2.2
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.15
Mutation Taster		=94/6	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: rs755212102; hg19: chr3-10858060;