rs74907974

chr15-26561007-G-Achr15-26561007-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000814.6(GABRB3):c.1005C>T(p.Gly335=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,124 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G335G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (30 hom.)
• Consequence: GABRB3 NM_000814.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.973

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-26561007-G-A is Benign according to our data. Variant chr15-26561007-G-A is described in ClinVar as [Benign]. Clinvar id is 256817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.973 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00849 (1293/152244) while in subpopulation AFR AF= 0.025 (1038/41546). AF 95% confidence interval is 0.0237. There are 24 homozygotes in gnomad4. There are 598 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB3	NM_000814.6	c.1005C>T	p.Gly335=	synonymous_variant	8/9	ENST00000311550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB3	ENST00000311550.10	c.1005C>T	p.Gly335=	synonymous_variant	8/9	1	NM_000814.6	P1

Frequencies

GnomAD3 genomes AF: 0.00847 AC: 1289 AN: 152126 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00350 AC: 881 AN: 251464 Hom.: 11 AF XY: 0.00322 AC XY: 437 AN XY: 135908

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00184 AC: 2684 AN: 1461880 Hom.: 30 Cov.: 33 AF XY: 0.00182 AC XY: 1320 AN XY: 727244

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.00483

GnomAD4 genome AF: 0.00849 AC: 1293 AN: 152244 Hom.: 24 Cov.: 33 AF XY: 0.00803 AC XY: 598 AN XY: 74430

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00316 Hom.: 1

Bravo AF: 0.0104

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 28, 2018

- -

Seizure Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2016

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	8.3
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs74907974; hg19: chr15-26806154;