rs1035751

Variant names:

• chr15-26698649-G-A
• rs1035751
• NM_000814.6:c.240+73753C>T

Variant summary

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

The NM_000814.6(GABRB3):​c.240+73753C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 152,204 control chromosomes in the GnomAD database, including 546 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 0.075 (546 hom., cov: 32)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.496
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000814.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	NM_000814.6	MANE Select	c.240+73753C>T		intron	N/A	NP_000805.1	P28472-1
	GABRB3	NM_021912.5		c.240+73753C>T		intron	N/A	NP_068712.1	X5DQY4
	GABRB3	NM_001191320.2		c.-16+17965C>T		intron	N/A	NP_001178249.1	P28472-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.240+73753C>T		intron	N/A	ENSP00000308725.5	P28472-1
	GABRB3	ENST00000541819.6	TSL:1	c.408+73753C>T		intron	N/A	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000299267.9	TSL:1	c.240+73753C>T		intron	N/A	ENSP00000299267.4	P28472-2

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11410 AN: 152086 Hom.: 545 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0939

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.0750 AC: 11413 AN: 152204 Hom.: 546 Cov.: 32 AF XY: 0.0751 AC XY: 5591 AN XY: 74432

African (AFR) AF: 0.0283 AC: 1176 AN: 41532

American (AMR) AF: 0.0937 AC: 1433 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3466

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5180

South Asian (SAS) AF: 0.110 AC: 532 AN: 4818

European-Finnish (FIN) AF: 0.0489 AC: 519 AN: 10612

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6799 AN: 67998

Other (OTH) AF: 0.106 AC: 223 AN: 2106

Alfa AF: 0.0938 Hom.: 577

Bravo AF: 0.0738

Asia WGS AF: 0.0910 AC: 316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.50
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1035751; hg19: chr15-26943796;