rs137938866

Variant names:

• chr9-122378834-T-A
• NM_000962.4:c.412T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-122378834-T-A
• chr9-122378834-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000962.4(PTGS1):​c.412T>A​(p.Trp138Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGS1	NM_000962.4	c.412T>A	p.Trp138Arg	missense_variant	Exon 5 of 11	ENST00000362012.7	NP_000953.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGS1	ENST00000362012.7	c.412T>A	p.Trp138Arg	missense_variant	Exon 5 of 11	1	NM_000962.4	ENSP00000354612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;D;D;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;.;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.4	.;.;M;M;.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-12	.;D;.;D;.;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;D;.;D;.;D;D
Polyphen		1.0	.;.;D;D;.;D;.
Vest4		0.93, 0.95, 0.95, 0.97
MutPred		0.73		.;.;Gain of disorder (P = 0.0052);Gain of disorder (P = 0.0052);.;Gain of disorder (P = 0.0052);.;
MVP		0.78
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-125141113;