X-152168369-G-C

Variant names:

• chrX-152168369-G-C
• rs76096542
• NM_000808.4:c.1338C>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000808.4(GABRA3):​c.1338C>G​(p.Thr446Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,210,176 control chromosomes in the GnomAD database, including 4 homozygotes. There are 393 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (1 hom., 29 hem., cov: 23)
  • Exomes 𝑓: 0.00098 (3 hom. 364 hem.)
• Consequence: GABRA3 NM_000808.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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]

ENSG00000231937 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant X-152168369-G-C is Benign according to our data. Variant chrX-152168369-G-C is described in ClinVar as [Benign]. Clinvar id is 782828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-152168369-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000984 (1080/1098059) while in subpopulation MID AF= 0.022 (91/4135). AF 95% confidence interval is 0.0184. There are 3 homozygotes in gnomad4_exome. There are 364 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 29 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA3	NM_000808.4	c.1338C>G	p.Thr446Thr	synonymous_variant	Exon 10 of 10	ENST00000370314.9	NP_000799.1
GABRA3	XM_006724811.4	c.*103C>G		3_prime_UTR_variant	Exon 9 of 9		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9	c.1338C>G	p.Thr446Thr	synonymous_variant	Exon 10 of 10	1	NM_000808.4	ENSP00000359337.4
GABRA3	ENST00000535043.1	c.1338C>G	p.Thr446Thr	synonymous_variant	Exon 10 of 10	1		ENSP00000443527.1
ENSG00000231937	ENST00000453915.1	n.501+3781G>C		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.000964 AC: 108 AN: 112064 Hom.: 1 Cov.: 23 AF XY: 0.000847 AC XY: 29 AN XY: 34220

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00416

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.000845

Gnomad OTH AF: 0.00395

GnomAD3 exomes AF: 0.00106 AC: 195 AN: 183459 Hom.: 0 AF XY: 0.00112 AC XY: 76 AN XY: 67901

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000314

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.000984 AC: 1080 AN: 1098059 Hom.: 3 Cov.: 31 AF XY: 0.00100 AC XY: 364 AN XY: 363413

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.00332

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000332

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000915

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome AF: 0.000954 AC: 107 AN: 112117 Hom.: 1 Cov.: 23 AF XY: 0.000846 AC XY: 29 AN XY: 34283

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.00415

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000845

Gnomad4 OTH AF: 0.00390

Alfa AF: 0.00161 Hom.: 10

Bravo AF: 0.00150

EpiCase AF: 0.00153

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

GABRA3-related disorder Benign:1

Sep 30, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.1
DANN	Benign	0.69

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

LitVar

Other links and lift over

dbSNP: rs76096542; hg19: chrX-151336841;