12-6839735-A-G

Variant names:

• chr12-6839735-A-G
• rs5440
• ENST00000612048.4:n.2018A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000612048.4(P3H3):​n.2018A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 441,808 control chromosomes in the GnomAD database, including 65,632 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 0.56 (24413 hom., cov: 32)
  • Exomes 𝑓: 0.52 (41219 hom.)
• Consequence: P3H3 ENST00000612048.4 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.170
• Publications: 23 publications found

Genes affected

P3H3 (HGNC:19318): (prolyl 3-hydroxylase 3) The protein encoded by this gene belongs to the leprecan family of proteoglycans, which function as collagen prolyl hydroxylases that are required for proper collagen biosynthesis, folding and assembly. This protein, like other family members, is thought to reside in the endoplasmic reticulum. Epigenetic inactivation of this gene is associated with breast and other cancers, suggesting that it may function as a tumor suppressor. [provided by RefSeq, Aug 2013]

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 Gene-Disease associations (from GenCC):

• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital stationary night blindness 1H

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H3	NM_014262.5	c.*274A>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000290510.10	NP_055077.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H3	ENST00000612048.4	n.2018A>G		non_coding_transcript_exon_variant	Exon 14 of 14	1
P3H3	ENST00000290510.10	c.*274A>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_014262.5	ENSP00000478600.1
P3H3	ENST00000536140.5	n.3115A>G		non_coding_transcript_exon_variant	Exon 16 of 16	2
GNB3	ENST00000540458.5	n.-219A>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84895 AN: 151950 Hom.: 24404 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.524 AC: 151827 AN: 289740 Hom.: 41219 Cov.: 3 AF XY: 0.528 AC XY: 78279 AN XY: 148176

African (AFR) AF: 0.701 AC: 7239 AN: 10328

American (AMR) AF: 0.487 AC: 6631 AN: 13614

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 5319 AN: 9928

East Asian (EAS) AF: 0.608 AC: 14601 AN: 24006

South Asian (SAS) AF: 0.669 AC: 12355 AN: 18474

European-Finnish (FIN) AF: 0.398 AC: 7007 AN: 17612

Middle Eastern (MID) AF: 0.575 AC: 788 AN: 1370

European-Non Finnish (NFE) AF: 0.501 AC: 88208 AN: 176196

Other (OTH) AF: 0.531 AC: 9679 AN: 18212

GnomAD4 genome AF: 0.559 AC: 84946 AN: 152068 Hom.: 24413 Cov.: 32 AF XY: 0.556 AC XY: 41292 AN XY: 74328

African (AFR) AF: 0.690 AC: 28633 AN: 41470

American (AMR) AF: 0.530 AC: 8106 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1875 AN: 3472

East Asian (EAS) AF: 0.621 AC: 3205 AN: 5158

South Asian (SAS) AF: 0.653 AC: 3150 AN: 4824

European-Finnish (FIN) AF: 0.401 AC: 4243 AN: 10586

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33850 AN: 67944

Other (OTH) AF: 0.569 AC: 1200 AN: 2110

Alfa AF: 0.513 Hom.: 23805

Bravo AF: 0.573

Asia WGS AF: 0.626 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.42
PhyloP100		-0.17
PromoterAI		0.068	Neutral
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: rs5440; hg19: chr12-6948899;