chr9-129748665-G-A

Position:

• chr9-129748665-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_004878.5(PTGES):​c.199C>T​(p.Arg67Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,424,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PTGES NM_004878.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

Genes affected

PTGES (HGNC:9599): (prostaglandin E synthase) The protein encoded by this gene is a glutathione-dependent prostaglandin E synthase. The expression of this gene has been shown to be induced by proinflammatory cytokine interleukin 1 beta (IL1B). Its expression can also be induced by tumor suppressor protein TP53, and may be involved in TP53 induced apoptosis. Knockout studies in mice suggest that this gene may contribute to the pathogenesis of collagen-induced arthritis and mediate acute pain during inflammatory responses. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site Loss of prostaglandin-E synthase activity. (size 0) in uniprot entity PTGES_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTGES	NM_004878.5	c.199C>T	p.Arg67Cys	missense_variant	2/3	ENST00000340607.5	NP_004869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTGES	ENST00000340607.5	c.199C>T	p.Arg67Cys	missense_variant	2/3	1	NM_004878.5	ENSP00000342385.4
PTGES	ENST00000481476.1	n.328C>T		non_coding_transcript_exon_variant	3/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1424608 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000279

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 11, 2022

The c.199C>T (p.R67C) alteration is located in exon 2 (coding exon 2) of the PTGES gene. This alteration results from a C to T substitution at nucleotide position 199, causing the arginine (R) at amino acid position 67 to be replaced by a cysteine (C). 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	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.95		Loss of disorder (P = 0.039);
MVP		0.84
MPC		0.85
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1413428703; hg19: chr9-132510944;