Genetic Variant PTGIS:p.Leu256Leu (chr20-49524145-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000961.4(PTGIS):c.768G>A(p.Leu256Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,614,182 control chromosomes in the GnomAD database, including 4,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.095 ( 854 hom., cov: 33)

Exomes 𝑓: 0.067 ( 3735 hom. )

Consequence

PTGIS
NM_000961.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.68

Publications

21 publications found

Variant links:

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)

PTGIS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 20-49524145-C-T is Benign according to our data. Variant chr20-49524145-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056980.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=1.67 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGIS	NM_000961.4 link	c.768G>A	p.Leu256Leu	synonymous_variant	Exon 6 of 10	ENST00000244043.5	NP_000952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGIS	ENST00000244043.5 link	c.768G>A	p.Leu256Leu	synonymous_variant	Exon 6 of 10	1	NM_000961.4	ENSP00000244043.3
PTGIS	ENST00000478971.1 link	n.589G>A		non_coding_transcript_exon_variant	Exon 5 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.0955

AC:

14527

AN:

152180

Hom.:

852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.0504

Gnomad EAS

AF:

0.0892

Gnomad SAS

AF:

0.0978

Gnomad FIN

AF:

0.0750

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0612

Gnomad OTH

AF:

0.0759

GnomAD2 exomes

AF:

0.0823

AC:

20685

AN:

251420

AF XY:

0.0792

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.0484

Gnomad EAS exome

AF:

0.0960

Gnomad FIN exome

AF:

0.0785

Gnomad NFE exome

AF:

0.0595

Gnomad OTH exome

AF:

0.0771

GnomAD4 exome

AF:

0.0668

AC:

97624

AN:

1461884

Hom.:

3735

Cov.:

AF XY:

0.0670

AC XY:

48707

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.167

AC:

5581

AN:

33478

American (AMR)

AF:

0.116

AC:

5185

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

1181

AN:

26136

East Asian (EAS)

AF:

0.0777

AC:

3085

AN:

39700

South Asian (SAS)

AF:

0.0864

AC:

7457

AN:

86258

European-Finnish (FIN)

AF:

0.0775

AC:

4142

AN:

53414

Middle Eastern (MID)

AF:

0.0856

AC:

494

AN:

5768

European-Non Finnish (NFE)

AF:

0.0593

AC:

65994

AN:

1112012

Other (OTH)

AF:

0.0746

AC:

4505

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

6541

13082

19622

26163

32704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2618

5236

7854

10472

13090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0955

AC:

14544

AN:

152298

Hom.:

854

Cov.:

AF XY:

0.0966

AC XY:

7190

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.159

AC:

6620

AN:

41560

American (AMR)

AF:

0.106

AC:

1615

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0504

AC:

175

AN:

3472

East Asian (EAS)

AF:

0.0894

AC:

462

AN:

5170

South Asian (SAS)

AF:

0.0966

AC:

466

AN:

4824

European-Finnish (FIN)

AF:

0.0750

AC:

797

AN:

10624

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0612

AC:

4161

AN:

68026

Other (OTH)

AF:

0.0761

AC:

161

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

681

1362

2042

2723

3404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0728

Hom.:

1907

Bravo

AF:

0.101

Asia WGS

AF:

0.105

AC:

365

AN:

3478

EpiCase

AF:

0.0636

EpiControl

AF:

0.0640

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PTGIS-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.0

(source)

DANN

Benign

0.66

PhyloP100

1.7

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over