15-27527592-G-T

Variant summary

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

The NM_033223.5(GABRG3):c.1025G>T(p.Ser342Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GABRG3 NM_033223.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.46

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, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.1025G>T	p.Ser342Ile	missense_variant	8/10	ENST00000615808.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.1025G>T	p.Ser342Ile	missense_variant	8/10	1	NM_033223.5	P1
	ENST00000556642.1	n.85+13521C>A		intron_variant, non_coding_transcript_variant		2
GABRG3	ENST00000333743.10	c.488G>T	p.Ser163Ile	missense_variant	5/7	5
GABRG3	ENST00000451330.2	c.314G>T	p.Ser105Ile	missense_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460798 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Feb 02, 2024

The c.1025G>T (p.S342I) alteration is located in exon 8 (coding exon 8) of the GABRG3 gene. This alteration results from a G to T substitution at nucleotide position 1025, causing the serine (S) at amino acid position 342 to be replaced by an isoleucine (I). 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	0.26
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.59	N
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.046	D;T
Polyphen		0.98	D;.
Vest4		0.66
MutPred		0.49		Loss of disorder (P = 0.0067);.;
MVP		0.59
MPC		1.4
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr15-27772738;