12-6847016-C-T

Variant names:

• chr12-6847016-C-T
• rs5445
• NM_002075.4:c.*118C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.286
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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	c.*118C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000229264.8	NP_002066.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15280 AN: 152140 Hom.: 1994 Cov.: 33

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.: 6 AF XY: 0.0391 AC XY: 10430 AN XY: 266548

African (AFR) AF: 0.281 AC: 4145 AN: 14774

American (AMR) AF: 0.125 AC: 3783 AN: 30204

Ashkenazi Jewish (ASJ) AF: 0.00823 AC: 133 AN: 16156

East Asian (EAS) AF: 0.325 AC: 10162 AN: 31286

South Asian (SAS) AF: 0.0115 AC: 606 AN: 52762

European-Finnish (FIN) AF: 0.00198 AC: 68 AN: 34332

Middle Eastern (MID) AF: 0.0557 AC: 123 AN: 2210

European-Non Finnish (NFE) AF: 0.00552 AC: 1636 AN: 296398

Other (OTH) AF: 0.0538 AC: 1515 AN: 28148

GnomAD4 genome AF: 0.101 AC: 15346 AN: 152258 Hom.: 2012 Cov.: 33 AF XY: 0.101 AC XY: 7514 AN XY: 74462

African (AFR) AF: 0.275 AC: 11431 AN: 41522

American (AMR) AF: 0.107 AC: 1637 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.301 AC: 1558 AN: 5172

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10628

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 68028

Other (OTH) AF: 0.0997 AC: 211 AN: 2116

Alfa AF: 0.0421 Hom.: 2492

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

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
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5445; hg19: chr12-6956180; COSMIC: COSV57529079; COSMIC: COSV57529079;