9-122383515-G-T

Position:

• chr9-122383515-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000962.4(PTGS1):​c.769G>T​(p.Asp257Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTGS1 NM_000962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.687

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32487178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTGS1	NM_000962.4	c.769G>T	p.Asp257Tyr	missense_variant	8/11	ENST00000362012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTGS1	ENST00000362012.7	c.769G>T	p.Asp257Tyr	missense_variant	8/11	1	NM_000962.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The c.769G>T (p.D257Y) alteration is located in exon 8 (coding exon 8) of the PTGS1 gene. This alteration results from a G to T substitution at nucleotide position 769, causing the aspartic acid (D) at amino acid position 257 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.97	D;D;.;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.27	T
Polyphen		0.98, 0.86	.;.;D;D;.;.;P;.
Vest4		0.51, 0.46, 0.50, 0.47
MutPred		0.45		.;.;Gain of phosphorylation at D257 (P = 0.0181);Gain of phosphorylation at D257 (P = 0.0181);.;.;Gain of phosphorylation at D257 (P = 0.0181);.;
MVP		0.41
MPC		0.73
ClinPred		0.97	D
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.74

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: rs992777872; hg19: chr9-125145794;