12-56666237-A-C

Position:

• chr12-56666237-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006601.7(PTGES3):​c.405T>G​(p.Asp135Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTGES3 NM_006601.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

Genes affected

PTGES3 (HGNC:16049): (prostaglandin E synthase 3) This gene encodes an enzyme that converts prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2). This protein functions as a co-chaperone with heat shock protein 90 (HSP90), localizing to response elements in DNA and disrupting transcriptional activation complexes. Alternative splicing results in multiple transcript variants. There are multiple pseudogenes of this gene on several different chromosomes. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20145127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTGES3	NM_006601.7	c.405T>G	p.Asp135Glu	missense_variant	6/8	ENST00000262033.11	NP_006592.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTGES3	ENST00000262033.11	c.405T>G	p.Asp135Glu	missense_variant	6/8	1	NM_006601.7	ENSP00000262033	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Jan 07, 2022

The c.405T>G (p.D135E) alteration is located in exon 6 (coding exon 6) of the PTGES3 gene. This alteration results from a T to G substitution at nucleotide position 405, causing the aspartic acid (D) at amino acid position 135 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
MutationTaster	Benign	0.93	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	N;.;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.17	T;.;T;T;T
Sift4G	Benign	0.83	.;T;.;.;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.40
MutPred		0.21		Gain of catalytic residue at G132 (P = 0.0191);.;.;.;.;
MVP		0.75
MPC		1.3
ClinPred		0.93	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.059

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-57060021;