ENST00000541819.6:c.249-1121G>T

Variant names:

• chr15-26773893-C-A
• rs4906901
• ENST00000541819.6:c.249-1121G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000541819.6(GABRB3):​c.249-1121G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 612,620 control chromosomes in the GnomAD database, including 263,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60168 hom., cov: 24)
  • Exomes 𝑓: 0.94 (203596 hom.)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.265
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-26773893-C-A is Benign according to our data. Variant chr15-26773893-C-A is described in CliVar as Benign. Clinvar id is 1239580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-26773893-C-A is described in CliVar as Benign. Clinvar id is 1239580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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
GABRB3	NM_021912.5	c.-169G>T		upstream_gene_variant			NP_068712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000541819.6	c.249-1121G>T		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000638099.1	c.-20+50G>T		intron_variant	Intron 1 of 8	5		ENSP00000490678.1
GABRB3	ENST00000557641.5	n.453-1121G>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.894 AC: 133733 AN: 149520 Hom.: 60139 Cov.: 24

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.809

Gnomad AMR AF: 0.930

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.985

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.901

GnomAD4 exome AF: 0.937 AC: 433761 AN: 463014 Hom.: 203596 Cov.: 5 AF XY: 0.939 AC XY: 228493 AN XY: 243230

African (AFR) AF: 0.775 AC: 9264 AN: 11950

American (AMR) AF: 0.938 AC: 17470 AN: 18632

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 12735 AN: 13460

East Asian (EAS) AF: 1.00 AC: 30362 AN: 30364

South Asian (SAS) AF: 0.980 AC: 44365 AN: 45270

European-Finnish (FIN) AF: 0.945 AC: 37227 AN: 39376

Middle Eastern (MID) AF: 0.890 AC: 1736 AN: 1950

European-Non Finnish (NFE) AF: 0.929 AC: 256448 AN: 276046

Other (OTH) AF: 0.930 AC: 24154 AN: 25966

GnomAD4 genome AF: 0.894 AC: 133805 AN: 149606 Hom.: 60168 Cov.: 24 AF XY: 0.898 AC XY: 65426 AN XY: 72880

African (AFR) AF: 0.780 AC: 31633 AN: 40576

American (AMR) AF: 0.931 AC: 14046 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3291 AN: 3462

East Asian (EAS) AF: 0.999 AC: 5009 AN: 5012

South Asian (SAS) AF: 0.984 AC: 4633 AN: 4706

European-Finnish (FIN) AF: 0.944 AC: 9410 AN: 9964

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

European-Non Finnish (NFE) AF: 0.932 AC: 62921 AN: 67514

Other (OTH) AF: 0.902 AC: 1874 AN: 2078

Alfa AF: 0.910 Hom.: 13131

Bravo AF: 0.885

Asia WGS AF: 0.976 AC: 3393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.52
PhyloP100		-0.27
PromoterAI		0.0098	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: rs4906901; hg19: chr15-27019040;