Genetic Variant GABRA3:p.Thr336Thr (chrX-152189865-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_000808.4(GABRA3):c.1008G>A(p.Thr336Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,207,093 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000033 ( 0 hom. 16 hem. )

Consequence

GABRA3
NM_000808.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.575

Publications

1 publications found

Variant links:

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

GABRA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant X-152189865-C-T is Benign according to our data. Variant chrX-152189865-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 726234.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.575 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 16 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.1008G>A	p.Thr336Thr	synonymous	Exon 9 of 10	NP_000799.1	P34903

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRA3	ENST00000370314.9	TSL:1 MANE Select	c.1008G>A	p.Thr336Thr	synonymous	Exon 9 of 10	ENSP00000359337.4	P34903
GABRA3	ENST00000535043.1	TSL:1	c.1008G>A	p.Thr336Thr	synonymous	Exon 9 of 10	ENSP00000443527.1	P34903
GABRA3	ENST00000862742.1		c.1008G>A	p.Thr336Thr	synonymous	Exon 10 of 11	ENSP00000532801.1

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

110538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000966

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:

0.0000567

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000220

AC:

AN:

181681

AF XY:

0.0000302

show subpopulations

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:

0.0000492

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1096501

Hom.:

Cov.:

AF XY:

0.0000442

AC XY:

AN XY:

361925

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26351

American (AMR)

AF:

0.00

AC:

AN:

35125

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30143

South Asian (SAS)

AF:

0.00

AC:

AN:

53938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4112

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

840894

Other (OTH)

AF:

0.0000652

AC:

AN:

46042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000362

AC:

AN:

110592

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

32844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30409

American (AMR)

AF:

0.0000965

AC:

AN:

10366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3482

South Asian (SAS)

AF:

0.00

AC:

AN:

2508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

52881

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.0000552

EpiControl

AF:

0.0000599

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.57

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over