dbSNP rs1236913: PTGS1:p.Trp8Arg (chr9-122371200-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000962.4(PTGS1):c.22T>C(p.Trp8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,608,790 control chromosomes in the GnomAD database, including 695,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.94 ( 68124 hom., cov: 36)

Exomes 𝑓: 0.93 ( 627235 hom. )

Consequence

PTGS1
NM_000962.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.893

Publications

69 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.077219E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGS1	NM_000962.4 link	c.22T>C	p.Trp8Arg	missense_variant	Exon 2 of 11	ENST00000362012.7	NP_000953.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGS1	ENST00000362012.7 link	c.22T>C	p.Trp8Arg	missense_variant	Exon 2 of 11	1	NM_000962.4	ENSP00000354612.2

Frequencies

GnomAD3 genomes

AF:

0.945

AC:

143824

AN:

152196

Hom.:

68079

Cov.:

show subpopulations

Gnomad AFR

AF:

0.985

Gnomad AMI

AF:

0.907

Gnomad AMR

AF:

0.934

Gnomad ASJ

AF:

0.965

Gnomad EAS

AF:

0.989

Gnomad SAS

AF:

0.821

Gnomad FIN

AF:

0.926

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.931

Gnomad OTH

AF:

0.938

GnomAD2 exomes

AF:

0.927

AC:

229337

AN:

247484

AF XY:

0.919

show subpopulations

Gnomad AFR exome

AF:

0.989

Gnomad AMR exome

AF:

0.931

Gnomad ASJ exome

AF:

0.963

Gnomad EAS exome

AF:

0.994

Gnomad FIN exome

AF:

0.925

Gnomad NFE exome

AF:

0.932

Gnomad OTH exome

AF:

0.939

GnomAD4 exome

AF:

0.927

AC:

1350776

AN:

1456476

Hom.:

627235

Cov.:

AF XY:

0.924

AC XY:

669748

AN XY:

724784

show subpopulations

African (AFR)

AF:

0.990

AC:

33134

AN:

33476

American (AMR)

AF:

0.931

AC:

41627

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

25173

AN:

26130

East Asian (EAS)

AF:

0.982

AC:

38981

AN:

39692

South Asian (SAS)

AF:

0.818

AC:

70522

AN:

86258

European-Finnish (FIN)

AF:

0.926

AC:

44587

AN:

48172

Middle Eastern (MID)

AF:

0.952

AC:

5489

AN:

5764

European-Non Finnish (NFE)

AF:

0.931

AC:

1034785

AN:

1111910

Other (OTH)

AF:

0.936

AC:

56478

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

6481

12963

19444

25926

32407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21562

43124

64686

86248

107810

<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:

0.945

AC:

143929

AN:

152314

Hom.:

68124

Cov.:

AF XY:

0.944

AC XY:

70312

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.985

AC:

40989

AN:

41594

American (AMR)

AF:

0.934

AC:

14301

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.965

AC:

3352

AN:

3472

East Asian (EAS)

AF:

0.989

AC:

5103

AN:

5158

South Asian (SAS)

AF:

0.821

AC:

3966

AN:

4828

European-Finnish (FIN)

AF:

0.926

AC:

9828

AN:

10618

Middle Eastern (MID)

AF:

0.959

AC:

282

AN:

294

European-Non Finnish (NFE)

AF:

0.931

AC:

63304

AN:

68014

Other (OTH)

AF:

0.935

AC:

1977

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

432

865

1297

1730

2162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.935

Hom.:

268775

Bravo

AF:

0.952

TwinsUK

AF:

0.927

AC:

3438

ALSPAC

AF:

0.934

AC:

3599

ESP6500AA

AF:

0.983

AC:

4329

ESP6500EA

AF:

0.929

AC:

7992

ExAC

AF:

0.926

AC:

112383

Asia WGS

AF:

0.894

AC:

3109

AN:

3478

EpiCase

AF:

0.931

EpiControl

AF:

0.934

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.8

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.077

T;T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.20

.;T;T;T;T

MetaRNN

Benign

9.1e-7

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.1

N;N;.;.;N

PhyloP100

-0.89

PrimateAI

Benign

0.44

PROVEAN

Benign

0.46

.;N;.;.;N

REVEL

Benign

0.032

Sift

Benign

0.73

.;T;.;.;T

Sift4G

Benign

0.60

T;T;.;.;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.18

MutPred

0.61

Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);

MPC

0.49

ClinPred

0.0014

GERP RS

0.39

PromoterAI

0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.050

gMVP

0.60

Mutation Taster

=300/0

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

Computational scores

Splicing

Publications

Other links and lift over