9-122392241-G-A

Variant names:

• chr9-122392241-G-A
• rs3842802
• NM_000962.4:c.1497G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000962.4(PTGS1):​c.1497G>A​(p.Ala499Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,607,794 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (56 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (71 hom.)
• Consequence: PTGS1 NM_000962.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-122392241-G-A is Benign according to our data. Variant chr9-122392241-G-A is described in ClinVar as Benign. ClinVar VariationId is 775276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	NM_000962.4	MANE Select	c.1497G>A	p.Ala499Ala	synonymous	Exon 11 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.1386G>A	p.Ala462Ala	synonymous	Exon 11 of 11	NP_542158.1
	PTGS1	NM_001271164.2		c.1353G>A	p.Ala451Ala	synonymous	Exon 10 of 10	NP_001258093.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTGS1	ENST00000362012.7	TSL:1 MANE Select	c.1497G>A	p.Ala499Ala	synonymous	Exon 11 of 11	ENSP00000354612.2
	PTGS1	ENST00000223423.8	TSL:1	c.1386G>A	p.Ala462Ala	synonymous	Exon 11 of 11	ENSP00000223423.4
	PTGS1	ENST00000863393.1		c.1551G>A	p.Ala517Ala	synonymous	Exon 12 of 12	ENSP00000533452.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2437 AN: 152108 Hom.: 56 Cov.: 31

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.00543 AC: 1363 AN: 250930 AF XY: 0.00443

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00439

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00246 AC: 3574 AN: 1455568 Hom.: 71 Cov.: 31 AF XY: 0.00231 AC XY: 1666 AN XY: 722560

African (AFR) AF: 0.0533 AC: 1776 AN: 33348

American (AMR) AF: 0.00682 AC: 304 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00430 AC: 112 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86104

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53348

Middle Eastern (MID) AF: 0.0122 AC: 70 AN: 5752

European-Non Finnish (NFE) AF: 0.000841 AC: 931 AN: 1106816

Other (OTH) AF: 0.00592 AC: 356 AN: 60098

GnomAD4 genome AF: 0.0160 AC: 2440 AN: 152226 Hom.: 56 Cov.: 31 AF XY: 0.0151 AC XY: 1123 AN XY: 74436

African (AFR) AF: 0.0521 AC: 2162 AN: 41524

American (AMR) AF: 0.00843 AC: 129 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68004

Other (OTH) AF: 0.0190 AC: 40 AN: 2110

Alfa AF: 0.00990 Hom.: 22

Bravo AF: 0.0184

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00160

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.2
DANN	Benign	0.35
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=89/11	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: rs3842802; hg19: chr9-125154520; COSMIC: COSV56290864;