NM_000814.6:c.*525G>A

Variant names:

• chr15-26547268-C-T
• rs11637141
• NM_000814.6:c.*525G>A

Variant summary

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

The NM_000814.6(GABRB3):​c.*525G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 350,814 control chromosomes in the GnomAD database, including 8,787 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 0.21 (3553 hom., cov: 32)
  • Exomes 𝑓: 0.22 (5234 hom.)
• Consequence: GABRB3 NM_000814.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• Publications: 8 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 (AMR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.*525G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.*525G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31783 AN: 151922 Hom.: 3551 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.0783

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.218 AC: 43316 AN: 198774 Hom.: 5234 Cov.: 0 AF XY: 0.218 AC XY: 22011 AN XY: 100790

African (AFR) AF: 0.148 AC: 908 AN: 6136

American (AMR) AF: 0.274 AC: 1912 AN: 6988

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 1965 AN: 7738

East Asian (EAS) AF: 0.0486 AC: 902 AN: 18568

South Asian (SAS) AF: 0.213 AC: 489 AN: 2300

European-Finnish (FIN) AF: 0.247 AC: 3497 AN: 14174

Middle Eastern (MID) AF: 0.197 AC: 203 AN: 1028

European-Non Finnish (NFE) AF: 0.237 AC: 30478 AN: 128482

Other (OTH) AF: 0.222 AC: 2962 AN: 13360

GnomAD4 genome AF: 0.209 AC: 31803 AN: 152040 Hom.: 3553 Cov.: 32 AF XY: 0.209 AC XY: 15506 AN XY: 74282

African (AFR) AF: 0.143 AC: 5947 AN: 41472

American (AMR) AF: 0.264 AC: 4037 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 886 AN: 3470

East Asian (EAS) AF: 0.0781 AC: 404 AN: 5174

South Asian (SAS) AF: 0.206 AC: 989 AN: 4812

European-Finnish (FIN) AF: 0.235 AC: 2481 AN: 10546

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.240 AC: 16307 AN: 67978

Other (OTH) AF: 0.190 AC: 400 AN: 2110

Alfa AF: 0.218 Hom.: 4933

Bravo AF: 0.207

Asia WGS AF: 0.157 AC: 547 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	8.5
DANN	Benign	0.75
PhyloP100		-0.0020
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: rs11637141; hg19: chr15-26792415;