15-27326938-C-T

Variant summary

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

The NM_033223.5(GABRG3):c.400C>T(p.Arg134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,866 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: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: GABRG3 NM_033223.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.400C>T	p.Arg134Cys	missense_variant	4/10	ENST00000615808.5
GABRG3	NM_001270873.2	c.400C>T	p.Arg134Cys	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.400C>T	p.Arg134Cys	missense_variant	4/10	1	NM_033223.5	P1
GABRG3	ENST00000554696.5	c.226C>T	p.Arg76Cys	missense_variant	2/6	3
GABRG3	ENST00000555083.5	c.400C>T	p.Arg134Cys	missense_variant	4/6	2
GABRG3	ENST00000333743.10	c.-138C>T		5_prime_UTR_variant	1/7	5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249300 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135248

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Apr 25, 2022

The c.400C>T (p.R134C) alteration is located in exon 4 (coding exon 4) of the GABRG3 gene. This alteration results from a C to T substitution at nucleotide position 400, causing the arginine (R) at amino acid position 134 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0070	D;D;T
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.63		Gain of catalytic residue at S136 (P = 0.0315);Gain of catalytic residue at S136 (P = 0.0315);.;
MVP		0.94
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.79

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: rs760375015; hg19: chr15-27572085; COSMIC: COSV61516910; COSMIC: COSV61516910;