rs5789

Variant names:

• chr9-122381694-C-A
• rs5789
• NM_000962.4:c.709C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-122381694-C-A
• chr9-122381694-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000962.4(PTGS1):​c.709C>A​(p.Leu237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,614,078 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (38 hom., cov: 33)
  • Exomes 𝑓: 0.024 (553 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 50 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066508353).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0181 (2751/152332) while in subpopulation AMR AF = 0.0291 (445/15290). AF 95% confidence interval is 0.0269. There are 38 homozygotes in GnomAd4. There are 1290 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	NM_000962.4	MANE Select	c.709C>A	p.Leu237Met	missense	Exon 7 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.709C>A	p.Leu237Met	missense	Exon 7 of 11	NP_542158.1	P23219-2
	PTGS1	NM_001271164.2		c.565C>A	p.Leu189Met	missense	Exon 6 of 10	NP_001258093.1	A0A087X296

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	ENST00000362012.7	TSL:1 MANE Select	c.709C>A	p.Leu237Met	missense	Exon 7 of 11	ENSP00000354612.2	P23219-1
	PTGS1	ENST00000223423.8	TSL:1	c.709C>A	p.Leu237Met	missense	Exon 7 of 11	ENSP00000223423.4	P23219-2
	PTGS1	ENST00000863393.1		c.763C>A	p.Leu255Met	missense	Exon 8 of 12	ENSP00000533452.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2752 AN: 152214 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0180 AC: 4526 AN: 251390 AF XY: 0.0180

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0236 AC: 34515 AN: 1461746 Hom.: 553 Cov.: 33 AF XY: 0.0232 AC XY: 16904 AN XY: 727170

African (AFR) AF: 0.00451 AC: 151 AN: 33480

American (AMR) AF: 0.0179 AC: 801 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 963 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00534 AC: 461 AN: 86254

European-Finnish (FIN) AF: 0.00403 AC: 215 AN: 53414

Middle Eastern (MID) AF: 0.0177 AC: 102 AN: 5768

European-Non Finnish (NFE) AF: 0.0273 AC: 30385 AN: 1111884

Other (OTH) AF: 0.0238 AC: 1437 AN: 60394

GnomAD4 genome AF: 0.0181 AC: 2751 AN: 152332 Hom.: 38 Cov.: 33 AF XY: 0.0173 AC XY: 1290 AN XY: 74492

African (AFR) AF: 0.00524 AC: 218 AN: 41586

American (AMR) AF: 0.0291 AC: 445 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4834

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10630

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1792 AN: 68032

Other (OTH) AF: 0.0289 AC: 61 AN: 2114

Alfa AF: 0.0245 Hom.: 246

Bravo AF: 0.0196

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0175 AC: 2129

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0301

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.35
Sift	Benign	0.060	T
Sift4G	Uncertain	0.045	D
Polyphen		0.37	B
Vest4		0.28
MPC		0.93
ClinPred		0.094	T
GERP RS		4.8
Varity_R		0.45
gMVP		0.38
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5789; hg19: chr9-125143973; COSMIC: COSV56291224;