12-6847298-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002075.4(GNB3):c.*400C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 220,912 control chromosomes in the GnomAD database, including 11,406 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 0.33 (8442 hom., cov: 32)
  • Exomes 𝑓: 0.28 (2964 hom.)
• Consequence: GNB3 NM_002075.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.*400C>T		3_prime_UTR_variant	10/10	ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.*400C>T		3_prime_UTR_variant	10/10	5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49539 AN: 152052 Hom.: 8432 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.280 AC: 19263 AN: 68742 Hom.: 2964 Cov.: 0 AF XY: 0.279 AC XY: 9875 AN XY: 35448

Gnomad4 AFR exome AF: 0.419

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.326 AC: 49573 AN: 152170 Hom.: 8442 Cov.: 32 AF XY: 0.321 AC XY: 23917 AN XY: 74402

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.346

Alfa AF: 0.306 Hom.: 8023

Bravo AF: 0.333

Asia WGS AF: 0.293 AC: 1016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.3
Dann	Benign	0.69

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: rs5446; hg19: chr12-6956462; COSMIC: COSV57529935; COSMIC: COSV57529935;