X-152189740-A-C

Variant names:

• chrX-152189740-A-C
• rs200749137
• NM_000808.4:c.1133T>G

Variant summary

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

The NM_000808.4(GABRA3):​c.1133T>G​(p.Leu378Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,903 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L378P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: GABRA3 NM_000808.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

GABRA3 (HGNC:4077): (gamma-aminobutyric acid type A receptor subunit alpha3) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. [provided by RefSeq, Jul 2008]

GABRA3 Gene-Disease associations (from GenCC):

• epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina

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=0.102541685).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000808.4. 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
	GABRA3	NM_000808.4	MANE Select	c.1133T>G	p.Leu378Arg	missense	Exon 9 of 10	NP_000799.1	P34903

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA3	ENST00000370314.9	TSL:1 MANE Select	c.1133T>G	p.Leu378Arg	missense	Exon 9 of 10	ENSP00000359337.4	P34903
	GABRA3	ENST00000535043.1	TSL:1	c.1133T>G	p.Leu378Arg	missense	Exon 9 of 10	ENSP00000443527.1	P34903
	GABRA3	ENST00000862742.1		c.1133T>G	p.Leu378Arg	missense	Exon 10 of 11	ENSP00000532801.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180678 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089903 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 356245

African (AFR) AF: 0.00 AC: 0 AN: 26243

American (AMR) AF: 0.00 AC: 0 AN: 35061

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19270

East Asian (EAS) AF: 0.00 AC: 0 AN: 30171

South Asian (SAS) AF: 0.00 AC: 0 AN: 53738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40443

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3378

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835860

Other (OTH) AF: 0.00 AC: 0 AN: 45739

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.64	T
Sift4G	Benign	0.55	T
Polyphen		0.0050	B
Vest4		0.27
MutPred		0.43		Gain of MoRF binding (P = 0.0267)
MVP		1.0
MPC		0.58
ClinPred		0.19	T
GERP RS		3.2
Varity_R		0.28
gMVP		0.69
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs200749137; hg19: chrX-151358212;