Genetic Variant PTGS1:p.Val481Ile (chr9-122390342-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000962.4(PTGS1):c.1441G>A(p.Val481Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00799 in 1,613,992 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0063 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0082 ( 57 hom. )

Consequence

PTGS1
NM_000962.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.51

Publications

26 publications found

Variant links:

Genes affected

PTGS1 (HGNC:9604): (prostaglandin-endoperoxide synthase 1) This is one of two genes encoding similar enzymes that catalyze the conversion of arachidonate to prostaglandin. The encoded protein regulates angiogenesis in endothelial cells, and is inhibited by nonsteroidal anti-inflammatory drugs such as aspirin. Based on its ability to function as both a cyclooxygenase and as a peroxidase, the encoded protein has been identified as a moonlighting protein. The protein may promote cell proliferation during tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2021]

PTGS1 Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 12
Inheritance: SD Classification: LIMITED Submitted by: ClinGen

PTGS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009871155).

BP6

Variant 9-122390342-G-A is Benign according to our data. Variant chr9-122390342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3024886.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGS1	NM_000962.4 link	c.1441G>A	p.Val481Ile	missense_variant	Exon 10 of 11	ENST00000362012.7	NP_000953.2	P23219-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGS1	ENST00000362012.7 link	c.1441G>A	p.Val481Ile	missense_variant	Exon 10 of 11	1	NM_000962.4	ENSP00000354612.2		P23219-1

Frequencies

GnomAD3 genomes

AF:

0.00630

AC:

959

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00855

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00718

AC:

1798

AN:

250416

AF XY:

0.00736

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00554

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00607

Gnomad NFE exome

AF:

0.00944

Gnomad OTH exome

AF:

0.00950

GnomAD4 exome

AF:

0.00816

AC:

11931

AN:

1461638

Hom.:

Cov.:

AF XY:

0.00825

AC XY:

5997

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00245

AC:

AN:

33478

American (AMR)

AF:

0.00584

AC:

261

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

309

AN:

26126

East Asian (EAS)

AF:

0.000302

AC:

AN:

39692

South Asian (SAS)

AF:

0.00760

AC:

655

AN:

86190

European-Finnish (FIN)

AF:

0.00743

AC:

397

AN:

53408

Middle Eastern (MID)

AF:

0.00642

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00877

AC:

9746

AN:

1111880

Other (OTH)

AF:

0.00715

AC:

432

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

635

1270

1905

2540

3175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00629

AC:

958

AN:

152354

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

480

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00255

AC:

106

AN:

41594

American (AMR)

AF:

0.00804

AC:

123

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00850

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00856

AC:

582

AN:

68030

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00814

Hom.:

Bravo

AF:

0.00616

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00734

AC:

891

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00747

EpiControl

AF:

0.00902

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTGS1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;.;T;T;T;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.87

D;D;.;D;D;D;D

MetaRNN

Benign

0.0099

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;N;N;.;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.92

.;N;.;N;.;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0040

.;D;.;D;.;D;D

Sift4G

Uncertain

0.010

.;D;.;D;.;D;D

Polyphen

0.10, 0.081

.;.;B;B;.;B;.

Vest4

0.23, 0.16, 0.23, 0.16

MVP

0.44

MPC

0.27

ClinPred

0.062

GERP RS

4.3

Varity_R

0.27

gMVP

0.63

Mutation Taster

=85/15

polymorphism

(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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chr9-122390342-G-A

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