20-49513169-G-C

Variant names:

• chr20-49513169-G-C
• rs5629
• NM_000961.4:c.1117C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000961.4(PTGIS):​c.1117C>G​(p.Arg373Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTGIS NM_000961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• Publications: 0 publications found

Genes affected

PTGIS (HGNC:9603): (prostaglandin I2 synthase) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. However, this protein is considered a member of the cytochrome P450 superfamily on the basis of sequence similarity rather than functional similarity. This endoplasmic reticulum membrane protein catalyzes the conversion of prostglandin H2 to prostacyclin (prostaglandin I2), a potent vasodilator and inhibitor of platelet aggregation. An imbalance of prostacyclin and its physiological antagonist thromboxane A2 contribute to the development of myocardial infarction, stroke, and atherosclerosis. [provided by RefSeq, Jul 2008]

PTGIS Gene-Disease associations (from GenCC):

• essential hypertension, genetic

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGIS	NM_000961.4	c.1117C>G	p.Arg373Gly	missense_variant	Exon 8 of 10	ENST00000244043.5	NP_000952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGIS	ENST00000244043.5	c.1117C>G	p.Arg373Gly	missense_variant	Exon 8 of 10	1	NM_000961.4	ENSP00000244043.3
PTGIS	ENST00000478971.1	n.938C>G		non_coding_transcript_exon_variant	Exon 7 of 9	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.29
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.58		Gain of catalytic residue at R373 (P = 0.0319);
MVP		0.84
MPC		0.19
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.57
gMVP		0.81
Mutation Taster		=76/24	polymorphism

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: rs5629; hg19: chr20-48129706; COSMIC: COSV54841344;