15-27026829-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033223.5(GABRG3):c.270+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,590,898 control chromosomes in the GnomAD database, including 27 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (15 hom.)
• Consequence: GABRG3 NM_033223.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001802
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.180

Genes affected

GABRG3 (HGNC:4088): (gamma-aminobutyric acid type A receptor subunit gamma3) This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. The protein encoded by this gene is a gamma subunit, which contains the benzodiazepine binding site. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-27026829-G-A is Benign according to our data. Variant chr15-27026829-G-A is described in ClinVar as [Benign]. Clinvar id is 769872.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1214/152300) while in subpopulation AFR AF= 0.0276 (1146/41576). AF 95% confidence interval is 0.0262. There are 12 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.270+8G>A		splice_region_variant, intron_variant		ENST00000615808.5
GABRG3	NM_001270873.2	c.270+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.270+8G>A		splice_region_variant, intron_variant		1	NM_033223.5	P1
GABRG3	ENST00000555083.5	c.270+8G>A		splice_region_variant, intron_variant		2
GABRG3	ENST00000553440.1	n.370G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1199 AN: 152182 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00184 AC: 428 AN: 232282 Hom.: 3 AF XY: 0.00130 AC XY: 164 AN XY: 126096

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000380

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.000712

GnomAD4 exome AF: 0.000744 AC: 1071 AN: 1438598 Hom.: 15 Cov.: 27 AF XY: 0.000584 AC XY: 418 AN XY: 715254

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000909

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152300 Hom.: 12 Cov.: 33 AF XY: 0.00810 AC XY: 603 AN XY: 74482

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00448 Hom.: 5

Bravo AF: 0.00923

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
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

Publications

LitVar

Other links and lift over

dbSNP: rs79691322; hg19: chr15-27271976;