Genetic Variant GNB3:c.*118C>T (chr12-6847016-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002075.4(GNB3):c.*118C>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 0.057 in 658,528 control chromosomes in the GnomAD database, including 4,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 2012 hom., cov: 33)

Exomes 𝑓: 0.044 ( 2622 hom. )

Consequence

GNB3
NM_002075.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.286

Variant links:

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]

GNB3 links:

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]

CDCA3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 12-6847016-C-T is Benign according to our data. Variant chr12-6847016-C-T is described in ClinVar as [Benign]. Clinvar id is 1260978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB3	NM_002075.4 link	c.*118C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000229264.8	NP_002066.1	P16520-1F1T0G5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8 link	c.*118C>T		3_prime_UTR_variant	Exon 10 of 10	5	NM_002075.4	ENSP00000229264.3		P16520-1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15280

AN:

152140

Hom.:

1994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.301

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.00556

Gnomad OTH

AF:

0.0989

GnomAD4 exome

AF:

0.0438

AC:

22171

AN:

506270

Hom.:

2622

Cov.:

AF XY:

0.0391

AC XY:

10430

AN XY:

266548

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.125

Gnomad4 ASJ exome

AF:

0.00823

Gnomad4 EAS exome

AF:

0.325

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.00198

Gnomad4 NFE exome

AF:

0.00552

Gnomad4 OTH exome

AF:

0.0538

GnomAD4 genome

AF:

0.101

AC:

15346

AN:

152258

Hom.:

2012

Cov.:

AF XY:

0.101

AC XY:

7514

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.275

Gnomad4 AMR

AF:

0.107

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.301

Gnomad4 SAS

AF:

0.0149

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00556

Gnomad4 OTH

AF:

0.0997

Alfa

AF:

0.0284

Hom.:

593

Bravo

AF:

0.119

Asia WGS

AF:

0.127

AC:

443

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.0

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over