chr20-49508057-A-C

Variant names:

• chr20-49508057-A-C
• rs777270308
• NM_000961.4:c.1366T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000961.4(PTGIS):​c.1366T>G​(p.Phe456Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PTGIS NM_000961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14424461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGIS	NM_000961.4	c.1366T>G	p.Phe456Val	missense_variant	Exon 10 of 10	ENST00000244043.5	NP_000952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGIS	ENST00000244043.5	c.1366T>G	p.Phe456Val	missense_variant	Exon 10 of 10	1	NM_000961.4	ENSP00000244043.3
PTGIS	ENST00000478971.1	n.1187T>G		non_coding_transcript_exon_variant	Exon 9 of 9	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250950 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.76	N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.083
Sift	Benign	0.068	T
Sift4G	Benign	0.19	T
Polyphen		0.035	B
Vest4		0.084
MutPred		0.59		Gain of helix (P = 0.1736);
MVP		0.18
MPC		0.17
ClinPred		0.34	T
GERP RS		-1.1
Varity_R		0.22
gMVP		0.76

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

Other links and lift over

dbSNP: rs777270308; hg19: chr20-48124594;