chr12-6845615-G-A

Position:

• chr12-6845615-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002075.4(GNB3):​c.729G>A​(p.Thr243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,612,744 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (18 hom.)
• Consequence: GNB3 NM_002075.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.90

Genes affected

GNB3 (HGNC:4400): (G protein subunit beta 3) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

CDCA3 (HGNC:14624): (cell division cycle associated 3) Predicted to be involved in cell division and protein ubiquitination. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-6845615-G-A is Benign according to our data. Variant chr12-6845615-G-A is described in ClinVar as [Benign]. Clinvar id is 774817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6845615-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.9 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB3	NM_002075.4	c.729G>A	p.Thr243=	synonymous_variant	9/10	ENST00000229264.8	NP_002066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8	c.729G>A	p.Thr243=	synonymous_variant	9/10	5	NM_002075.4	ENSP00000229264	P1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00210 AC: 526 AN: 250248 Hom.: 5 AF XY: 0.00258 AC XY: 349 AN XY: 135440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00898

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00179 AC: 2609 AN: 1460438 Hom.: 18 Cov.: 31 AF XY: 0.00201 AC XY: 1459 AN XY: 726578

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00832

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74470

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00103

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147480203; hg19: chr12-6954779;