rs4363842

Variant names:

• chr15-26774258-A-G
• rs4363842
• ENST00000541819.6:c.249-1486T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-26774258-A-G
• chr15-26774258-A-T

Variant summary

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

The ENST00000541819.6(GABRB3):​c.249-1486T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 151,754 control chromosomes in the GnomAD database, including 60,787 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 0.89 (60787 hom., cov: 31)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.854
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.249-1486T>C		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000557641.5	n.453-1486T>C		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135285 AN: 151638 Hom.: 60750 Cov.: 31

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.900

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

GnomAD4 genome AF: 0.892 AC: 135378 AN: 151754 Hom.: 60787 Cov.: 31 AF XY: 0.895 AC XY: 66424 AN XY: 74188

African (AFR) AF: 0.773 AC: 31925 AN: 41280

American (AMR) AF: 0.928 AC: 14174 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3299 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5112 AN: 5120

South Asian (SAS) AF: 0.984 AC: 4733 AN: 4812

European-Finnish (FIN) AF: 0.943 AC: 9973 AN: 10578

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63275 AN: 67912

Other (OTH) AF: 0.901 AC: 1900 AN: 2108

Alfa AF: 0.903 Hom.: 7723

Bravo AF: 0.884

Asia WGS AF: 0.973 AC: 3382 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.6
DANN	Benign	0.56
PhyloP100		-0.85
PromoterAI		-0.031	Neutral
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: rs4363842; hg19: chr15-27019405;