rs5794

Variant names:

• chr9-122390342-G-A
• rs5794
• NM_000962.4:c.1441G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-122390342-G-A
• chr9-122390342-G-T

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• 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
• Publications: 26 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 -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 VariationId is 3024886.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 7 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.1441G>A	p.Val481Ile	missense	Exon 10 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.1330G>A	p.Val444Ile	missense	Exon 10 of 11	NP_542158.1	P23219-2
	PTGS1	NM_001271164.2		c.1297G>A	p.Val433Ile	missense	Exon 9 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.1441G>A	p.Val481Ile	missense	Exon 10 of 11	ENSP00000354612.2	P23219-1
	PTGS1	ENST00000223423.8	TSL:1	c.1330G>A	p.Val444Ile	missense	Exon 10 of 11	ENSP00000223423.4	P23219-2
	PTGS1	ENST00000863393.1		c.1495G>A	p.Val499Ile	missense	Exon 11 of 12	ENSP00000533452.1

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

GnomAD2 exomes AF: 0.00718 AC: 1798 AN: 250416 AF XY: 0.00736

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 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

African (AFR) AF: 0.00245 AC: 82 AN: 33478

American (AMR) AF: 0.00584 AC: 261 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 309 AN: 26126

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39692

South Asian (SAS) AF: 0.00760 AC: 655 AN: 86190

European-Finnish (FIN) AF: 0.00743 AC: 397 AN: 53408

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5766

European-Non Finnish (NFE) AF: 0.00877 AC: 9746 AN: 1111880

Other (OTH) AF: 0.00715 AC: 432 AN: 60394

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

African (AFR) AF: 0.00255 AC: 106 AN: 41594

American (AMR) AF: 0.00804 AC: 123 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

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

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00856 AC: 582 AN: 68030

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00814 Hom.: 23

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.5
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.10	B
Vest4		0.23
MVP		0.44
MPC		0.27
ClinPred		0.062	T
GERP RS		4.3
Varity_R		0.27
gMVP		0.63
Mutation Taster		=85/15	polymorphism

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