9-122378015-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_000962.4(PTGS1):c.211C>T(p.Pro71Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000504 in 1,611,488 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 3 hom. )

Consequence

PTGS1
NM_000962.4 missense, splice_region

Scores

Splicing: ADA: 0.9919

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

Publications

5 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, AD, AR Classification: LIMITED Submitted by: ClinGen

PTGS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High Homozygotes in GnomAdExome4 at 3 SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000962.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTGS1	NM_000962.4	MANE Select	c.211C>T	p.Pro71Ser	missense splice_region	Exon 3 of 11	NP_000953.2
PTGS1	NM_080591.3		c.211C>T	p.Pro71Ser	missense splice_region	Exon 3 of 11	NP_542158.1	P23219-2
PTGS1	NM_001271164.2		c.211C>T	p.Pro71Ser	missense splice_region	Exon 3 of 10	NP_001258093.1	A0A087X296

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTGS1	ENST00000362012.7	TSL:1 MANE Select	c.211C>T	p.Pro71Ser	missense splice_region	Exon 3 of 11	ENSP00000354612.2	P23219-1
PTGS1	ENST00000223423.8	TSL:1	c.211C>T	p.Pro71Ser	missense splice_region	Exon 3 of 11	ENSP00000223423.4	P23219-2
PTGS1	ENST00000863393.1		c.211C>T	p.Pro71Ser	missense splice_region	Exon 3 of 12	ENSP00000533452.1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

296

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00584

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.000669

AC:

167

AN:

249466

AF XY:

0.000519

show subpopulations

Gnomad AFR exome

AF:

0.00726

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000354

AC:

517

AN:

1459132

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

235

AN XY:

726072

show subpopulations

African (AFR)

AF:

0.00667

AC:

223

AN:

33448

American (AMR)

AF:

0.000895

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51614

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000163

AC:

181

AN:

1111248

Other (OTH)

AF:

0.00104

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00194

AC:

295

AN:

152356

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00580

AC:

241

AN:

41584

American (AMR)

AF:

0.00170

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000849

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.020

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.8

PhyloP100

6.2

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.47

Sift

Benign

0.080

Sift4G

Uncertain

0.0090

Polyphen

0.95

Vest4

0.53

MVP

0.92

MPC

0.85

ClinPred

0.032

GERP RS

4.8

Varity_R

0.64

gMVP

0.84

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.77

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over