NM_012293.3:c.1657G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_012293.3(PXDN):c.1657G>A(p.Glu553Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000815 in 1,594,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

PXDN
NM_012293.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.54

Variant links:

Genes affected

PXDN (HGNC:14966): (peroxidasin) This gene encodes a heme-containing peroxidase that is secreted into the extracellular matrix. It is involved in extracellular matrix formation, and may function in the physiological and pathological fibrogenic response in fibrotic kidney. Mutations in this gene cause corneal opacification and other ocular anomalies, and also microphthalmia and anterior segment dysgenesis. [provided by RefSeq, Aug 2014]

PXDN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.28240687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDN	NM_012293.3 link	c.1657G>A	p.Glu553Lys	missense_variant	Exon 13 of 23	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PXDN	ENST00000252804.9 link	c.1657G>A	p.Glu553Lys	missense_variant	Exon 13 of 23	1	NM_012293.3	ENSP00000252804.4	Q92626-1
PXDN	ENST00000433670.5 link	c.1642G>A	p.Glu548Lys	missense_variant	Exon 13 of 16	1		ENSP00000402738.1	H7C1W1
PXDN	ENST00000425171.2 link	c.1585G>A	p.Glu529Lys	missense_variant	Exon 12 of 16	5		ENSP00000398363.2	C9J4I9
PXDN	ENST00000478155.5 link	n.2249G>A		non_coding_transcript_exon_variant	Exon 6 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000186

AC:

AN:

215122

Hom.:

AF XY:

0.0000257

AC XY:

AN XY:

116538

show subpopulations

Gnomad AFR exome

AF:

0.0000824

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000624

Gnomad SAS exome

AF:

0.0000377

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000693

AC:

AN:

1442454

Hom.:

Cov.:

AF XY:

0.00000839

AC XY:

AN XY:

715528

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000514

Gnomad4 SAS exome

AF:

0.0000484

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 7

Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 553 of the PXDN protein (p.Glu553Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs755097189, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with PXDN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Nov 21, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

0.041

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.035

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.15

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.63

Sift4G

Benign

0.79

Polyphen

0.64

Vest4

0.55

MutPred

0.47

Gain of methylation at E553 (P = 0.0042);

MVP

0.64

MPC

0.52

ClinPred

0.44

GERP RS

4.5

Varity_R

0.20

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over