Genetic Variant PTGR2:p.Arg11Leu (chr14-73858894-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001146154.2(PTGR2):c.32G>T(p.Arg11Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,672 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R11P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTGR2
NM_001146154.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.72

Publications

0 publications found

Variant links:

Genes affected

PTGR2 (HGNC:20149): (prostaglandin reductase 2) This gene encodes an enzyme involved in the metabolism of prostaglandins. The encoded protein catalyzes the NADPH-dependent conversion of 15-keto-prostaglandin E2 to 15-keto-13,14-dihydro-prostaglandin E2. This protein may also be involved in regulating activation of the peroxisome proliferator-activated receptor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

PTGR2 links:

ENSG00000258653 (HGNC:):

ENSG00000258653 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTGR2	NM_001146154.2 link	c.32G>T	p.Arg11Leu	missense_variant	Exon 2 of 10	ENST00000555661.6	NP_001139626.1	Q8N8N7-1V9HW32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTGR2	ENST00000555661.6 link	c.32G>T	p.Arg11Leu	missense_variant	Exon 2 of 10	1	NM_001146154.2	ENSP00000452280.1		Q8N8N7-1
ENSG00000258653	ENST00000556551.2 link	n.32G>T		non_coding_transcript_exon_variant	Exon 2 of 22	2		ENSP00000451484.1		G3V3Y1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458672

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725762

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109854

Other (OTH)

AF:

0.00

AC:

AN:

60184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;.;D

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Pathogenic

3.4

M;M;M

PhyloP100

6.7

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.7

D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.88

MutPred

0.70

Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);

MVP

0.18

MPC

0.44

ClinPred

1.0

GERP RS

4.8

Varity_R

0.78

gMVP

0.74

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over