rs3842789

Variant names:

• chr9-122377962-G-A
• rs3842789
• NM_000962.4:c.158G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000962.4(PTGS1):​c.158G>A​(p.Arg53His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.108
• Publications: 11 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010848433).

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.158G>A	p.Arg53His	missense	Exon 3 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.158G>A	p.Arg53His	missense	Exon 3 of 11	NP_542158.1	P23219-2
	PTGS1	NM_001271164.2		c.158G>A	p.Arg53His	missense	Exon 3 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.158G>A	p.Arg53His	missense	Exon 3 of 11	ENSP00000354612.2	P23219-1
	PTGS1	ENST00000223423.8	TSL:1	c.158G>A	p.Arg53His	missense	Exon 3 of 11	ENSP00000223423.4	P23219-2
	PTGS1	ENST00000863393.1		c.158G>A	p.Arg53His	missense	Exon 3 of 12	ENSP00000533452.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251174 AF XY: 0.000221

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 727162

African (AFR) AF: 0.00233 AC: 78 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111994

Other (OTH) AF: 0.000182 AC: 11 AN: 60388

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00111 AC XY: 83 AN XY: 74476

African (AFR) AF: 0.00358 AC: 149 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.00100

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.050	N
PhyloP100		0.11
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.12
Sift	Benign	0.40	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.69
MPC		0.34
ClinPred		0.0094	T
GERP RS		-0.22
Varity_R		0.099
gMVP		0.55
Mutation Taster		=87/13	polymorphism

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: rs3842789; hg19: chr9-125140241; COSMIC: COSV99793138;