rs3842788

Variant names:

• chr9-122377927-G-A
• rs3842788
• NM_000962.4:c.123G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-122377927-G-A
• chr9-122377927-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_001271367.2(PTGS1):​c.-204-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,613,848 control chromosomes in the GnomAD database, including 3,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1356 hom., cov: 33)
  • Exomes 𝑓: 0.032 (1843 hom.)
• Consequence: PTGS1 NM_001271367.2 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.48
• Publications: 36 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 -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06461087 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 6, new splice context is: actatccatgccaacaccAGggc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 9-122377927-G-A is Benign according to our data. Variant chr9-122377927-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271367.2. 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.123G>A	p.Gln41Gln	synonymous	Exon 3 of 11	NP_000953.2
	PTGS1	NM_080591.3		c.123G>A	p.Gln41Gln	synonymous	Exon 3 of 11	NP_542158.1	P23219-2
	PTGS1	NM_001271164.2		c.123G>A	p.Gln41Gln	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.123G>A	p.Gln41Gln	synonymous	Exon 3 of 11	ENSP00000354612.2	P23219-1
	PTGS1	ENST00000223423.8	TSL:1	c.123G>A	p.Gln41Gln	synonymous	Exon 3 of 11	ENSP00000223423.4	P23219-2
	PTGS1	ENST00000863393.1		c.123G>A	p.Gln41Gln	synonymous	Exon 3 of 12	ENSP00000533452.1

Frequencies

GnomAD3 genomes AF: 0.0917 AC: 13950 AN: 152126 Hom.: 1357 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.0622

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0462 AC: 11613 AN: 251310 AF XY: 0.0427

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0637

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0320 AC: 46799 AN: 1461604 Hom.: 1843 Cov.: 31 AF XY: 0.0319 AC XY: 23211 AN XY: 727138

African (AFR) AF: 0.264 AC: 8820 AN: 33454

American (AMR) AF: 0.0299 AC: 1337 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 789 AN: 26128

East Asian (EAS) AF: 0.0659 AC: 2616 AN: 39698

South Asian (SAS) AF: 0.0407 AC: 3510 AN: 86246

European-Finnish (FIN) AF: 0.0278 AC: 1480 AN: 53328

Middle Eastern (MID) AF: 0.0912 AC: 526 AN: 5768

European-Non Finnish (NFE) AF: 0.0226 AC: 25081 AN: 1111888

Other (OTH) AF: 0.0437 AC: 2640 AN: 60380

GnomAD4 genome AF: 0.0918 AC: 13970 AN: 152244 Hom.: 1356 Cov.: 33 AF XY: 0.0895 AC XY: 6665 AN XY: 74448

African (AFR) AF: 0.252 AC: 10441 AN: 41502

American (AMR) AF: 0.0459 AC: 703 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3470

East Asian (EAS) AF: 0.0617 AC: 319 AN: 5166

South Asian (SAS) AF: 0.0385 AC: 186 AN: 4830

European-Finnish (FIN) AF: 0.0256 AC: 272 AN: 10630

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1678 AN: 68024

Other (OTH) AF: 0.0758 AC: 160 AN: 2110

Alfa AF: 0.0489 Hom.: 1518

Bravo AF: 0.0998

Asia WGS AF: 0.0520 AC: 179 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0311

ClinVar

ClinVar submissions

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	-0.47
CADD	Benign	15
DANN	Benign	0.78
PhyloP100		3.5
Mutation Taster		=288/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3842788; hg19: chr9-125140206; COSMIC: COSV56292305;