rs5794

chr9-122390342-G-Achr9-122390342-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000962.4(PTGS1):c.1441G>A(p.Val481Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00799 in 1,613,992 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (57 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.51

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009871155).
• BP6: Variant 9-122390342-G-A is Benign according to our data. Variant chr9-122390342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3024886.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTGS1	NM_000962.4	c.1441G>A	p.Val481Ile	missense_variant	10/11	ENST00000362012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTGS1	ENST00000362012.7	c.1441G>A	p.Val481Ile	missense_variant	10/11	1	NM_000962.4	P1

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 959 AN: 152236 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00855

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00718 AC: 1798 AN: 250416 Hom.: 11 AF XY: 0.00736 AC XY: 996 AN XY: 135334

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00554

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00646

Gnomad FIN exome AF: 0.00607

Gnomad NFE exome AF: 0.00944

Gnomad OTH exome AF: 0.00950

GnomAD4 exome AF: 0.00816 AC: 11931 AN: 1461638 Hom.: 57 Cov.: 31 AF XY: 0.00825 AC XY: 5997 AN XY: 727122

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00584

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00760

Gnomad4 FIN exome AF: 0.00743

Gnomad4 NFE exome AF: 0.00877

Gnomad4 OTH exome AF: 0.00715

GnomAD4 genome AF: 0.00629 AC: 958 AN: 152354 Hom.: 7 Cov.: 31 AF XY: 0.00644 AC XY: 480 AN XY: 74498

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.00856

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00851 Hom.: 15

Bravo AF: 0.00616

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00734 AC: 891

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00902

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

PTGS1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D;D;.;D;D;D;D
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Uncertain	0.48	T
Polyphen		0.10, 0.081	.;.;B;B;.;B;.
Vest4		0.23, 0.16, 0.23, 0.16
MVP		0.44
MPC		0.27
ClinPred		0.062	T
GERP RS		4.3
Varity_R		0.27
gMVP		0.63

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: rs5794; hg19: chr9-125152621; COSMIC: COSV99793129;