15-27532602-C-T

Position:

• chr15-27532602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP5_Moderate BP4 BP7

The NM_033223.5(GABRG3):​c.1125C>T​(p.Asn375=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG3 NM_033223.5 splice_region, synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.16

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-27532602-C-T is Pathogenic according to our data. Variant chr15-27532602-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 870529.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG3	NM_033223.5	c.1125C>T	p.Asn375=	splice_region_variant, synonymous_variant	10/10	ENST00000615808.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG3	ENST00000615808.5	c.1125C>T	p.Asn375=	splice_region_variant, synonymous_variant	10/10	1	NM_033223.5	P1
	ENST00000556642.1	n.85+8511G>A		intron_variant, non_coding_transcript_variant		2
GABRG3	ENST00000333743.10	c.588C>T	p.Asn196=	splice_region_variant, synonymous_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Angelman syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kamineni Academy of Medical Sciences & Research Centre, Kamineni Hospitals

Mar 08, 2020

The GABRG3 1125C>T was identified in a 9 year/female who has developmental delay, microcephaly, gait ataxia, absent speech and behavioral issues. She was subjected to Chromosomal microarray (CMA) and exome sequencing. CMA reported multiple absence of heterozygosity regions with 15q11.2 being the primary. Methylation studies indicated both the parental alleles to be present ruling out Angelman syndrome by imprinting defects. Raw data of CMA and exome were assessed and the reported variant was a single heterozygous change in the long stretch of 7 mb absence of heterozygosity region. Genes associated with phenotype were also analysed for possible differential diagnoses, however, no clinically significant changes were observed. Reported variant is novel and was identified to be damaging by in silico analysis. Segregation in parents and normal healthy siblings revealed it is de novo. The condition is Angelman like, since the gene is in the AS-PWS critical region, GABRG3 should be evaluated in individuals with AS features but with a negative UBE3A mutation status -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1891450501; hg19: chr15-27777748;