9-122378008-C-T

Variant names:

• chr9-122378008-C-T
• rs3842790
• NM_000962.4:c.204C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000962.4(PTGS1):​c.204C>T​(p.Cys68Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,612,484 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (44 hom.)
• Consequence: PTGS1 NM_000962.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.24
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-122378008-C-T is Benign according to our data. Variant chr9-122378008-C-T is described in ClinVar as Benign. ClinVar VariationId is 786578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2172/152366) while in subpopulation AFR AF = 0.0485 (2015/41584). AF 95% confidence interval is 0.0467. There are 45 homozygotes in GnomAd4. There are 1023 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.204C>T	p.Cys68Cys	synonymous	Exon 3 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.204C>T	p.Cys68Cys	synonymous	Exon 3 of 11	NP_542158.1	P23219-2
	PTGS1	NM_001271164.2		c.204C>T	p.Cys68Cys	synonymous	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.204C>T	p.Cys68Cys	synonymous	Exon 3 of 11	ENSP00000354612.2	P23219-1
	PTGS1	ENST00000223423.8	TSL:1	c.204C>T	p.Cys68Cys	synonymous	Exon 3 of 11	ENSP00000223423.4	P23219-2
	PTGS1	ENST00000863393.1		c.204C>T	p.Cys68Cys	synonymous	Exon 3 of 12	ENSP00000533452.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2170 AN: 152248 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00386 AC: 966 AN: 249966 AF XY: 0.00282

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00149 AC: 2170 AN: 1460118 Hom.: 44 Cov.: 31 AF XY: 0.00130 AC XY: 944 AN XY: 726550

African (AFR) AF: 0.0469 AC: 1570 AN: 33454

American (AMR) AF: 0.00369 AC: 165 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52092

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5764

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1111668

Other (OTH) AF: 0.00333 AC: 201 AN: 60364

GnomAD4 genome AF: 0.0143 AC: 2172 AN: 152366 Hom.: 45 Cov.: 33 AF XY: 0.0137 AC XY: 1023 AN XY: 74504

African (AFR) AF: 0.0485 AC: 2015 AN: 41584

American (AMR) AF: 0.00732 AC: 112 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00760 Hom.: 23

Bravo AF: 0.0158

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	PTGS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		2.2
Mutation Taster		=257/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3842790; hg19: chr9-125140287;