15-26977119-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_033223.5(GABRG3):c.171A>G(p.Glu57=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,613,788 control chromosomes in the GnomAD database, including 505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (275 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (230 hom.)
• Consequence: GABRG3 NM_033223.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.414

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=-0.46).
• BP6: Variant 15-26977119-A-G is Benign according to our data. Variant chr15-26977119-A-G is described in ClinVar as [Benign]. Clinvar id is 768687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.414 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.171A>G	p.Glu57=	synonymous_variant	2/10	ENST00000615808.5
GABRG3	NM_001270873.2	c.171A>G	p.Glu57=	synonymous_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.171A>G	p.Glu57=	synonymous_variant	2/10	1	NM_033223.5	P1
GABRG3	ENST00000555083.5	c.171A>G	p.Glu57=	synonymous_variant	2/6	2
GABRG3	ENST00000553440.1	n.263A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4856 AN: 152192 Hom.: 275 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00776 AC: 1933 AN: 248986 Hom.: 93 AF XY: 0.00580 AC XY: 783 AN XY: 135094

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00491

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00325 AC: 4754 AN: 1461478 Hom.: 230 Cov.: 32 AF XY: 0.00283 AC XY: 2061 AN XY: 727004

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00548

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.0319 AC: 4858 AN: 152310 Hom.: 275 Cov.: 32 AF XY: 0.0296 AC XY: 2203 AN XY: 74492

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0175 Hom.: 64

Bravo AF: 0.0359

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000356

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	-0.46
Cadd	Benign	6.6
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: rs35752220; hg19: chr15-27222266;