rs755097189

chr2-1662095-C-T

Variant summary

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

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. 13/20 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.54

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]

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=0.28240687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXDN	NM_012293.3	c.1657G>A	p.Glu553Lys	missense_variant	13/23	ENST00000252804.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXDN	ENST00000252804.9	c.1657G>A	p.Glu553Lys	missense_variant	13/23	1	NM_012293.3	P1
PXDN	ENST00000433670.5	c.1645G>A	p.Glu549Lys	missense_variant	13/16	1
PXDN	ENST00000425171.2	c.1585G>A	p.Glu529Lys	missense_variant	12/16	5
PXDN	ENST00000478155.5	n.2249G>A		non_coding_transcript_exon_variant	6/15	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 33

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: 4 AN: 215122 Hom.: 0 AF XY: 0.0000257 AC XY: 3 AN XY: 116538

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: 10 AN: 1442454 Hom.: 0 Cov.: 31 AF XY: 0.00000839 AC XY: 6 AN XY: 715528

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: 3 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

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.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anterior segment dysgenesis 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2019

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.041
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.15	N
MutationTaster	Benign	0.82	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.63	T
Sift4G	Benign	0.79	T
Polyphen		0.64	P
Vest4		0.55
MutPred		0.47		Gain of methylation at E553 (P = 0.0042);
MVP		0.64
MPC		0.52
ClinPred		0.44	T
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

Other links and lift over

dbSNP: rs755097189; hg19: chr2-1665867; COSMIC: COSV53239196; COSMIC: COSV53239196;