15-27480771-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_033223.5(GABRG3):c.696C>T(p.Ile232=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 1,613,704 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (109 hom.)
• Consequence: GABRG3 NM_033223.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.736

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 15-27480771-C-T is Benign according to our data. Variant chr15-27480771-C-T is described in ClinVar as [Benign]. Clinvar id is 778095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.736 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00884 (12919/1461412) while in subpopulation MID AF= 0.0187 (108/5768). AF 95% confidence interval is 0.0159. There are 109 homozygotes in gnomad4_exome. There are 6369 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.696C>T	p.Ile232=	synonymous_variant	6/10	ENST00000615808.5
GABRG3	NM_001270873.2	c.696C>T	p.Ile232=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.696C>T	p.Ile232=	synonymous_variant	6/10	1	NM_033223.5	P1
GABRG3	ENST00000333743.10	c.159C>T	p.Ile53=	synonymous_variant	3/7	5
GABRG3	ENST00000554696.5	c.522C>T	p.Ile174=	synonymous_variant	4/6	3
GABRG3	ENST00000555083.5	c.696C>T	p.Ile232=	synonymous_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152174 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00907

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00874 AC: 2171 AN: 248458 Hom.: 29 AF XY: 0.00872 AC XY: 1175 AN XY: 134786

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.0562

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.00233

Gnomad FIN exome AF: 0.00349

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00884 AC: 12919 AN: 1461412 Hom.: 109 Cov.: 31 AF XY: 0.00876 AC XY: 6369 AN XY: 726936

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.0549

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00254

Gnomad4 FIN exome AF: 0.00358

Gnomad4 NFE exome AF: 0.00907

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152292 Hom.: 8 Cov.: 33 AF XY: 0.00694 AC XY: 517 AN XY: 74476

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.00906

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0103 Hom.: 9

Bravo AF: 0.00782

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0119

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	-0.33
Cadd	Benign	6.3
Dann	Benign	0.89

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: rs77771286; hg19: chr15-27725917; COSMIC: COSV61535287; COSMIC: COSV61535287;