NM_000962.4:c.323G>A

Variant names:

• chr9-122378544-G-A
• rs5787
• NM_000962.4:c.323G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000962.4(PTGS1):​c.323G>A​(p.Arg108Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03
• Publications: 13 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18291515).

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.323G>A	p.Arg108Gln	missense	Exon 4 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.323G>A	p.Arg108Gln	missense	Exon 4 of 11	NP_542158.1
	PTGS1	NM_001271164.2		c.323G>A	p.Arg108Gln	missense	Exon 4 of 10	NP_001258093.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	ENST00000362012.7	TSL:1 MANE Select	c.323G>A	p.Arg108Gln	missense	Exon 4 of 11	ENSP00000354612.2
	PTGS1	ENST00000223423.8	TSL:1	c.323G>A	p.Arg108Gln	missense	Exon 4 of 11	ENSP00000223423.4
	PTGS1	ENST00000619306.5	TSL:5	c.323G>A	p.Arg108Gln	missense	Exon 4 of 10	ENSP00000483540.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251440 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112010

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74472

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.0
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.082	T
Sift4G	Benign	0.17	T
Polyphen		0.94	P
Vest4		0.53
MutPred		0.65		Gain of catalytic residue at R108 (P = 0.0478)
MVP		0.87
MPC		0.45
ClinPred		0.18	T
GERP RS		5.7
Varity_R		0.51
gMVP		0.89
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5787; hg19: chr9-125140823;