rs200630597

Variant names:

• chrX-152256002-G-A
• rs200630597
• NM_000808.4:c.331-4C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000808.4(GABRA3):​c.331-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,168,858 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 165 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00041 (0 hom. 157 hem.)
• Consequence: GABRA3 NM_000808.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002727
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.209
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-152256002-G-A is Benign according to our data. Variant chrX-152256002-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 742959.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA3	NM_000808.4	c.331-4C>T		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000370314.9	NP_000799.1
GABRA3	XM_006724811.4	c.331-4C>T		splice_region_variant, intron_variant	Intron 4 of 8		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9	c.331-4C>T		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_000808.4	ENSP00000359337.4
GABRA3	ENST00000535043.1	c.331-4C>T		splice_region_variant, intron_variant	Intron 4 of 9	1		ENSP00000443527.1
GABRA3	ENST00000417858.1	n.-4C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000259 AC: 26 AN: 100496 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

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: 0.000431

Gnomad OTH AF: 0.000719

GnomAD2 exomes AF: 0.000192 AC: 34 AN: 177503 AF XY: 0.000239

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: 0.000376

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000407 AC: 435 AN: 1068362 Hom.: 0 Cov.: 27 AF XY: 0.000467 AC XY: 157 AN XY: 336118

African (AFR) AF: 0.00 AC: 0 AN: 25852

American (AMR) AF: 0.0000285 AC: 1 AN: 35115

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19185

East Asian (EAS) AF: 0.00 AC: 0 AN: 30099

South Asian (SAS) AF: 0.000131 AC: 7 AN: 53441

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40103

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.000500 AC: 408 AN: 815355

Other (OTH) AF: 0.000421 AC: 19 AN: 45160

GnomAD4 genome AF: 0.000259 AC: 26 AN: 100496 Hom.: 0 Cov.: 23 AF XY: 0.000297 AC XY: 8 AN XY: 26968

African (AFR) AF: 0.0000425 AC: 1 AN: 23506

American (AMR) AF: 0.000200 AC: 2 AN: 9980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2497

East Asian (EAS) AF: 0.00 AC: 0 AN: 3307

South Asian (SAS) AF: 0.00 AC: 0 AN: 2329

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000431 AC: 22 AN: 51083

Other (OTH) AF: 0.000719 AC: 1 AN: 1390

Alfa AF: 0.000477 Hom.: 3

Bravo AF: 0.000185

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

GABRA3-related disorder Benign:1

Aug 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

May 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.51
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.090		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: rs200630597; hg19: chrX-151424474;