15-27480772-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_033223.5(GABRG3):c.697G>A(p.Val233Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GABRG3 NM_033223.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.79

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007251799).
• BP6: Variant 15-27480772-G-A is Benign according to our data. Variant chr15-27480772-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3035580.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.697G>A	p.Val233Met	missense_variant	6/10	ENST00000615808.5
GABRG3	NM_001270873.2	c.697G>A	p.Val233Met	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.697G>A	p.Val233Met	missense_variant	6/10	1	NM_033223.5	P1
GABRG3	ENST00000333743.10	c.160G>A	p.Val54Met	missense_variant	3/7	5
GABRG3	ENST00000554696.5	c.523G>A	p.Val175Met	missense_variant	4/6	3
GABRG3	ENST00000555083.5	c.697G>A	p.Val233Met	missense_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000491 AC: 122 AN: 248488 Hom.: 0 AF XY: 0.000438 AC XY: 59 AN XY: 134798

Gnomad AFR exome AF: 0.000780

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00542

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1461418 Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 126 AN XY: 726940

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00431

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74470

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000376 Hom.: 1

Bravo AF: 0.000604

ESP6500AA AF: 0.000793 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000513 AC: 62

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GABRG3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.0073	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	0.76	D;N
PrimateAI	Uncertain	0.74	T
Sift4G	Uncertain	0.045	D;D;T;D
Polyphen		0.47	P;.;.;.
Vest4		0.32
MVP		0.60
MPC		0.91
ClinPred		0.043	T
GERP RS		3.6
Varity_R		0.25
gMVP		0.52

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: rs201602655; hg19: chr15-27725918;