Genetic Variant NM_000961.4:c.1117C>A (chr20-49513169-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_000961.4(PTGIS):c.1117C>A(p.Arg373Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,868 control chromosomes in the GnomAD database, including 48,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.22 ( 3965 hom., cov: 31)

Exomes 𝑓: 0.24 ( 44655 hom. )

Consequence

PTGIS
NM_000961.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.45

Publications

47 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 20-49513169-G-T is Benign according to our data. Variant chr20-49513169-G-T is described in ClinVar as Benign. ClinVar VariationId is 3060885.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=2.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGIS	NM_000961.4 link	c.1117C>A	p.Arg373Arg	synonymous_variant	Exon 8 of 10	ENST00000244043.5	NP_000952.1	Q16647

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGIS	ENST00000244043.5 link	c.1117C>A	p.Arg373Arg	synonymous_variant	Exon 8 of 10	1	NM_000961.4	ENSP00000244043.3		Q16647
PTGIS	ENST00000478971.1 link	n.938C>A		non_coding_transcript_exon_variant	Exon 7 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33454

AN:

151912

Hom.:

3966

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.227

Gnomad SAS

AF:

0.275

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.267

GnomAD2 exomes

AF:

0.253

AC:

63525

AN:

251076

AF XY:

0.257

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.313

Gnomad ASJ exome

AF:

0.343

Gnomad EAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.207

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.274

GnomAD4 exome

AF:

0.244

AC:

356948

AN:

1461836

Hom.:

44655

Cov.:

AF XY:

0.246

AC XY:

179006

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.136

AC:

4561

AN:

33480

American (AMR)

AF:

0.308

AC:

13753

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

9065

AN:

26134

East Asian (EAS)

AF:

0.224

AC:

8874

AN:

39700

South Asian (SAS)

AF:

0.285

AC:

24591

AN:

86258

European-Finnish (FIN)

AF:

0.211

AC:

11279

AN:

53380

Middle Eastern (MID)

AF:

0.364

AC:

2099

AN:

5768

European-Non Finnish (NFE)

AF:

0.240

AC:

267012

AN:

1111998

Other (OTH)

AF:

0.260

AC:

15714

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

18274

36547

54821

73094

91368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9184

18368

27552

36736

45920

<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:

0.220

AC:

33456

AN:

152032

Hom.:

3965

Cov.:

AF XY:

0.224

AC XY:

16668

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.136

AC:

5623

AN:

41476

American (AMR)

AF:

0.303

AC:

4625

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1135

AN:

3466

East Asian (EAS)

AF:

0.227

AC:

1166

AN:

5140

South Asian (SAS)

AF:

0.277

AC:

1332

AN:

4812

European-Finnish (FIN)

AF:

0.215

AC:

2276

AN:

10582

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16505

AN:

67968

Other (OTH)

AF:

0.265

AC:

559

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1318

2636

3955

5273

6591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.233

Hom.:

7826

Bravo

AF:

0.221

Asia WGS

AF:

0.250

AC:

866

AN:

3478

EpiCase

AF:

0.263

EpiControl

AF:

0.263

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

-0.36

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

2.5

Mutation Taster

=100/0

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