rs5789

chr9-122381694-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000962.4(PTGS1):c.709C>A(p.Leu237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,614,078 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (38 hom., cov: 33)
  • Exomes 𝑓: 0.024 (553 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066508353).
• BP6: Variant 9-122381694-C-A is Benign according to our data. Variant chr9-122381694-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0181 (2751/152332) while in subpopulation AMR AF= 0.0291 (445/15290). AF 95% confidence interval is 0.0269. There are 38 homozygotes in gnomad4. There are 1290 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTGS1	NM_000962.4	c.709C>A	p.Leu237Met	missense_variant	7/11	ENST00000362012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTGS1	ENST00000362012.7	c.709C>A	p.Leu237Met	missense_variant	7/11	1	NM_000962.4	P1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2752 AN: 152214 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0180 AC: 4526 AN: 251390 Hom.: 73 AF XY: 0.0180 AC XY: 2439 AN XY: 135856

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00614

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0236 AC: 34515 AN: 1461746 Hom.: 553 Cov.: 33 AF XY: 0.0232 AC XY: 16904 AN XY: 727170

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0369

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00534

Gnomad4 FIN exome AF: 0.00403

Gnomad4 NFE exome AF: 0.0273

Gnomad4 OTH exome AF: 0.0238

GnomAD4 genome AF: 0.0181 AC: 2751 AN: 152332 Hom.: 38 Cov.: 33 AF XY: 0.0173 AC XY: 1290 AN XY: 74492

Gnomad4 AFR AF: 0.00524

Gnomad4 AMR AF: 0.0291

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00724

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0260 Hom.: 142

Bravo AF: 0.0196

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0175 AC: 2129

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0301

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;.;T;T;T;T;T
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
Polyphen		0.37, 0.34	.;.;B;B;.;.;B;.
Vest4		0.28, 0.22, 0.30, 0.24
MPC		0.93
ClinPred		0.094	T
GERP RS		4.8
Varity_R		0.45
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs5789; hg19: chr9-125143973; COSMIC: COSV56291224;