chr12-6839718-A-C

Variant names:

• chr12-6839718-A-C
• rs5439
• ENST00000612048.4:n.2001A>C

Variant summary

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

The ENST00000612048.4(P3H3):​n.2001A>C 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 0.0901 in 492,052 control chromosomes in the GnomAD database, including 2,632 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 0.073 (604 hom., cov: 33)
  • Exomes 𝑓: 0.098 (2028 hom.)
• Consequence: P3H3 ENST00000612048.4 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.194
• Publications: 16 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000612048.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H3	NM_014262.5	MANE Select	c.*257A>C		3_prime_UTR	Exon 15 of 15	NP_055077.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H3	ENST00000612048.4	TSL:1	n.2001A>C		non_coding_transcript_exon	Exon 14 of 14
	P3H3	ENST00000290510.10	TSL:1 MANE Select	c.*257A>C		3_prime_UTR	Exon 15 of 15	ENSP00000478600.1
	P3H3	ENST00000536140.5	TSL:2	n.3098A>C		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.0733 AC: 11158 AN: 152178 Hom.: 601 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0729

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0520

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.0819

GnomAD4 exome AF: 0.0977 AC: 33179 AN: 339756 Hom.: 2028 Cov.: 3 AF XY: 0.102 AC XY: 17823 AN XY: 174776

African (AFR) AF: 0.0160 AC: 178 AN: 11102

American (AMR) AF: 0.0640 AC: 1006 AN: 15722

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 1060 AN: 11184

East Asian (EAS) AF: 0.182 AC: 4880 AN: 26814

South Asian (SAS) AF: 0.182 AC: 4450 AN: 24444

European-Finnish (FIN) AF: 0.0522 AC: 1128 AN: 21592

Middle Eastern (MID) AF: 0.0996 AC: 155 AN: 1556

European-Non Finnish (NFE) AF: 0.0895 AC: 18483 AN: 206584

Other (OTH) AF: 0.0886 AC: 1839 AN: 20758

GnomAD4 genome AF: 0.0732 AC: 11155 AN: 152296 Hom.: 604 Cov.: 33 AF XY: 0.0748 AC XY: 5566 AN XY: 74454

African (AFR) AF: 0.0170 AC: 706 AN: 41556

American (AMR) AF: 0.0729 AC: 1116 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 341 AN: 3468

East Asian (EAS) AF: 0.180 AC: 933 AN: 5176

South Asian (SAS) AF: 0.196 AC: 946 AN: 4828

European-Finnish (FIN) AF: 0.0520 AC: 553 AN: 10626

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6241 AN: 68014

Other (OTH) AF: 0.0815 AC: 172 AN: 2110

Alfa AF: 0.0875 Hom.: 682

Bravo AF: 0.0714

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.64
DANN	Benign	0.63
PhyloP100		-0.19
PromoterAI		0.020	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: rs5439; hg19: chr12-6948882;