chr9-122371228-C-T

Variant names:

• chr9-122371228-C-T
• rs3842787
• NM_000962.4:c.50C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000962.4(PTGS1):​c.50C>T​(p.Pro17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 1,607,982 control chromosomes in the GnomAD database, including 4,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.082 (637 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3650 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 102 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 Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016974807).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	NM_000962.4	MANE Select	c.50C>T	p.Pro17Leu	missense	Exon 2 of 11	NP_000953.2
	PTGS1	NM_001271368.2		c.-248C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001258297.1
	PTGS1	NM_001271166.2		c.-278C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001258095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	ENST00000362012.7	TSL:1 MANE Select	c.50C>T	p.Pro17Leu	missense	Exon 2 of 11	ENSP00000354612.2
	PTGS1	ENST00000223423.8	TSL:1	c.50C>T	p.Pro17Leu	missense	Exon 2 of 11	ENSP00000223423.4
	PTGS1	ENST00000540753.6	TSL:2	c.-248C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	ENSP00000437709.1

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12488 AN: 152226 Hom.: 635 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0649

GnomAD2 exomes AF: 0.0588 AC: 14508 AN: 246842 AF XY: 0.0558

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0743

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0657 AC: 95581 AN: 1455638 Hom.: 3650 Cov.: 38 AF XY: 0.0636 AC XY: 46101 AN XY: 724406

African (AFR) AF: 0.137 AC: 4576 AN: 33474

American (AMR) AF: 0.0276 AC: 1233 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0739 AC: 1930 AN: 26128

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39692

South Asian (SAS) AF: 0.0148 AC: 1280 AN: 86256

European-Finnish (FIN) AF: 0.125 AC: 5943 AN: 47466

Middle Eastern (MID) AF: 0.0312 AC: 180 AN: 5762

European-Non Finnish (NFE) AF: 0.0689 AC: 76600 AN: 1111796

Other (OTH) AF: 0.0635 AC: 3834 AN: 60348

GnomAD4 genome AF: 0.0820 AC: 12492 AN: 152344 Hom.: 637 Cov.: 33 AF XY: 0.0822 AC XY: 6125 AN XY: 74500

African (AFR) AF: 0.132 AC: 5480 AN: 41588

American (AMR) AF: 0.0325 AC: 497 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 239 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4830

European-Finnish (FIN) AF: 0.142 AC: 1506 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0663 AC: 4510 AN: 68024

Other (OTH) AF: 0.0643 AC: 136 AN: 2116

Alfa AF: 0.0687 Hom.: 1478

Bravo AF: 0.0778

TwinsUK AF: 0.0674 AC: 250

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.138 AC: 608

ESP6500EA AF: 0.0681 AC: 586

ExAC AF: 0.0606 AC: 7354

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0611

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.086
DANN	Benign	0.79
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.11
Sift	Benign	0.49	T
Sift4G	Benign	0.32	T
Polyphen		0.33	B
Vest4		0.14
MPC		0.28
ClinPred		0.0026	T
GERP RS		1.3
PromoterAI		0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.019
gMVP		0.55
Mutation Taster		=95/5	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: rs3842787; hg19: chr9-125133507; COSMIC: COSV56291601; COSMIC: COSV56291601;