15-27527589-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033223.5(GABRG3):c.1022C>G(p.Ser341Cys) variant causes a missense change involving the alteration of a non-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: 3.17

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.1022C>G	p.Ser341Cys	missense_variant	8/10	ENST00000615808.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.1022C>G	p.Ser341Cys	missense_variant	8/10	1	NM_033223.5	P1
	ENST00000556642.1	n.85+13524G>C		intron_variant, non_coding_transcript_variant		2
GABRG3	ENST00000333743.10	c.485C>G	p.Ser162Cys	missense_variant	5/7	5
GABRG3	ENST00000451330.2	c.311C>G	p.Ser104Cys	missense_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

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

Dec 09, 2023

The c.1022C>G (p.S341C) alteration is located in exon 8 (coding exon 8) of the GABRG3 gene. This alteration results from a C to G substitution at nucleotide position 1022, causing the serine (S) at amino acid position 341 to be replaced by a cysteine (C). 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	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;.
Vest4		0.62
MutPred		0.62		Loss of disorder (P = 0.0116);.;
MVP		0.82
MPC		1.5
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.35
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: chr15-27772735;