15-27480668-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033223.5(GABRG3):c.593A>C(p.Glu198Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GABRG3 NM_033223.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.93

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.593A>C	p.Glu198Ala	missense_variant	6/10	ENST00000615808.5
GABRG3	NM_001270873.2	c.593A>C	p.Glu198Ala	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.593A>C	p.Glu198Ala	missense_variant	6/10	1	NM_033223.5	P1
GABRG3	ENST00000333743.10	c.56A>C	p.Glu19Ala	missense_variant	3/7	5
GABRG3	ENST00000554696.5	c.419A>C	p.Glu140Ala	missense_variant	4/6	3
GABRG3	ENST00000555083.5	c.593A>C	p.Glu198Ala	missense_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2022

The c.593A>C (p.E198A) alteration is located in exon 6 (coding exon 6) of the GABRG3 gene. This alteration results from a A to C substitution at nucleotide position 593, causing the glutamic acid (E) at amino acid position 198 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.1	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.16	B;.;.;.
Vest4		0.84
MutPred		0.79		Gain of MoRF binding (P = 0.0512);Gain of MoRF binding (P = 0.0512);.;.;
MVP		0.80
MPC		0.68
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-27725814;