Genetic Variant PTGS1:p.Gln41Gln (chr9-122377927-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000962.4(PTGS1):c.123G>A(p.Gln41Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,613,848 control chromosomes in the GnomAD database, including 3,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 1356 hom., cov: 33)

Exomes 𝑓: 0.032 ( 1843 hom. )

Consequence

PTGS1
NM_000962.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.48

Publications

35 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 9-122377927-G-A is Benign according to our data. Variant chr9-122377927-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGS1	NM_000962.4 link	c.123G>A	p.Gln41Gln	synonymous_variant	Exon 3 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.123G>A	p.Gln41Gln	synonymous_variant	Exon 3 of 11	1	NM_000962.4	ENSP00000354612.2		P23219-1

Frequencies

GnomAD3 genomes

AF:

0.0917

AC:

13950

AN:

152126

Hom.:

1357

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.0460

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.0622

Gnomad SAS

AF:

0.0379

Gnomad FIN

AF:

0.0256

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0247

Gnomad OTH

AF:

0.0766

GnomAD2 exomes

AF:

0.0462

AC:

11613

AN:

251310

AF XY:

0.0427

show subpopulations

Gnomad AFR exome

AF:

0.260

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.0637

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.0254

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0320

AC:

46799

AN:

1461604

Hom.:

1843

Cov.:

AF XY:

0.0319

AC XY:

23211

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.264

AC:

8820

AN:

33454

American (AMR)

AF:

0.0299

AC:

1337

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

789

AN:

26128

East Asian (EAS)

AF:

0.0659

AC:

2616

AN:

39698

South Asian (SAS)

AF:

0.0407

AC:

3510

AN:

86246

European-Finnish (FIN)

AF:

0.0278

AC:

1480

AN:

53328

Middle Eastern (MID)

AF:

0.0912

AC:

526

AN:

5768

European-Non Finnish (NFE)

AF:

0.0226

AC:

25081

AN:

1111888

Other (OTH)

AF:

0.0437

AC:

2640

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2300

4599

6899

9198

11498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1102

2204

3306

4408

5510

<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:

0.0918

AC:

13970

AN:

152244

Hom.:

1356

Cov.:

AF XY:

0.0895

AC XY:

6665

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.252

AC:

10441

AN:

41502

American (AMR)

AF:

0.0459

AC:

703

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

107

AN:

3470

East Asian (EAS)

AF:

0.0617

AC:

319

AN:

5166

South Asian (SAS)

AF:

0.0385

AC:

186

AN:

4830

European-Finnish (FIN)

AF:

0.0256

AC:

272

AN:

10630

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0247

AC:

1678

AN:

68024

Other (OTH)

AF:

0.0758

AC:

160

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

582

1164

1747

2329

2911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0489

Hom.:

1518

Bravo

AF:

0.0998

Asia WGS

AF:

0.0520

AC:

179

AN:

3478

EpiCase

AF:

0.0306

EpiControl

AF:

0.0311

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 08, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

3.5

Mutation Taster

=288/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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