NM_000808.4:c.1144-6C>T

Variant names:

• chrX-152168569-G-A
• rs201465927
• NM_000808.4:c.1144-6C>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.1144-6C>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 0.0000195 in 1,179,502 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 0.000054 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 8 hem.)
• Consequence: GABRA3 NM_000808.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001196
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.49
• 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

ENSG00000231937 (HGNC:58378):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-152168569-G-A is Benign according to our data. Variant chrX-152168569-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3025484.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

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.1144-6C>T		splice_region intron	N/A	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.1144-6C>T		splice_region intron	N/A	ENSP00000359337.4	P34903
	GABRA3	ENST00000535043.1	TSL:1	c.1144-6C>T		splice_region intron	N/A	ENSP00000443527.1	P34903
	GABRA3	ENST00000862742.1		c.1144-6C>T		splice_region intron	N/A	ENSP00000532801.1

Frequencies

GnomAD3 genomes AF: 0.0000538 AC: 6 AN: 111465 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000327

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: 0.0000941

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000339 AC: 6 AN: 176745 AF XY: 0.0000160

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: 0.0000634

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.0000159 AC: 17 AN: 1068037 Hom.: 0 Cov.: 27 AF XY: 0.0000238 AC XY: 8 AN XY: 336455

African (AFR) AF: 0.00 AC: 0 AN: 25706

American (AMR) AF: 0.00 AC: 0 AN: 34413

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18841

East Asian (EAS) AF: 0.00 AC: 0 AN: 29993

South Asian (SAS) AF: 0.00 AC: 0 AN: 52545

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40351

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4013

European-Non Finnish (NFE) AF: 0.0000196 AC: 16 AN: 817199

Other (OTH) AF: 0.0000222 AC: 1 AN: 44976

GnomAD4 genome AF: 0.0000538 AC: 6 AN: 111465 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33663

African (AFR) AF: 0.0000327 AC: 1 AN: 30622

American (AMR) AF: 0.00 AC: 0 AN: 10498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2617

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53115

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.51
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs201465927; hg19: chrX-151337041;