ENST00000541819.6:c.201-945A>G

Variant names:

• chr15-26817359-T-C
• rs4477673
• ENST00000541819.6:c.201-945A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000541819.6(GABRB3):​c.201-945A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 151,686 control chromosomes in the GnomAD database, including 11,321 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (11321 hom., cov: 30)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.116
• Publications: 5 publications found

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]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000541819.6	c.201-945A>G		intron_variant	Intron 1 of 9	1		ENSP00000442408.2

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56281 AN: 151568 Hom.: 11292 Cov.: 30

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.407

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.372 AC: 56363 AN: 151686 Hom.: 11321 Cov.: 30 AF XY: 0.370 AC XY: 27447 AN XY: 74090

African (AFR) AF: 0.481 AC: 19882 AN: 41368

American (AMR) AF: 0.496 AC: 7558 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1299 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1896 AN: 5146

South Asian (SAS) AF: 0.419 AC: 2010 AN: 4796

European-Finnish (FIN) AF: 0.202 AC: 2121 AN: 10482

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20358 AN: 67888

Other (OTH) AF: 0.408 AC: 855 AN: 2096

Alfa AF: 0.348 Hom.: 2257

Bravo AF: 0.397

Asia WGS AF: 0.437 AC: 1521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.0
DANN	Benign	0.59
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4477673; hg19: chr15-27062506;