rs1555383878

chr15-26772467-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_000814.6(GABRB3):c.175C>T(p.Pro59Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GABRB3 NM_000814.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.61

Genes affected

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Extracellular (size 219) in uniprot entity GBRB3_HUMAN there are 39 pathogenic changes around while only 7 benign (85%) in NM_000814.6
• PP2: Missense variant where missense usually causes diseases, GABRB3
• BP4: Computational evidence support a benign effect (MetaRNN=0.39559034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB3	NM_000814.6	c.175C>T	p.Pro59Ser	missense_variant, splice_region_variant	3/9	ENST00000311550.10
GABRB3	NM_021912.5	c.175C>T	p.Pro59Ser	missense_variant, splice_region_variant	3/9
GABRB3	NM_001278631.2	c.-177C>T		splice_region_variant, 5_prime_UTR_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB3	ENST00000311550.10	c.175C>T	p.Pro59Ser	missense_variant, splice_region_variant	3/9	1	NM_000814.6	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458070 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725330

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: 0.00000721

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2018

The p.P59S variant (also known as c.175C>T), located in coding exon 3 of the GABRB3 gene, results from a C to T substitution at nucleotide position 175. The proline at codon 59 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2020

This sequence change replaces proline with serine at codon 59 of the GABRB3 protein (p.Pro59Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. In summary, this variant has uncertain impact on GABRB3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a GABRB3-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.90	L;.;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.93	N;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.074	T;T;D;.
Sift4G	Benign	0.26	T;T;T;.
Polyphen		0.0060	B;B;B;.
Vest4		0.090
MutPred		0.40		.;Loss of catalytic residue at P115 (P = 0.1268);.;.;
MVP		0.44
MPC		1.2
ClinPred		0.31	T
GERP RS		4.6
Varity_R		0.27
gMVP		0.80

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: rs1555383878; hg19: chr15-27017614;