rs372395551

chr2-1644706-C-Achr2-1644706-C-Gchr2-1644706-C-T

Variant summary

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

The NM_012293.3(PXDN):c.3655G>T(p.Val1219Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,599,610 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

PXDN
NM_012293.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.80

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXDN	NM_012293.3 linkuse as main transcript	c.3655G>T	p.Val1219Leu	missense_variant	18/23	ENST00000252804.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXDN	ENST00000252804.9 linkuse as main transcript	c.3655G>T	p.Val1219Leu	missense_variant	18/23	1	NM_012293.3	P1	Q92626-1
PXDN	ENST00000477093.1 linkuse as main transcript	n.297G>T		non_coding_transcript_exon_variant	2/3	4
PXDN	ENST00000478155.5 linkuse as main transcript	n.2743G>T		non_coding_transcript_exon_variant	10/15	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000823

AC:

AN:

243132

Hom.:

AF XY:

0.0000832

AC XY:

AN XY:

132222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000513

Gnomad NFE exome

AF:

0.0000811

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000497

AC:

AN:

1447450

Hom.:

Cov.:

AF XY:

0.0000445

AC XY:

AN XY:

719432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.000283

Gnomad4 NFE exome

AF:

0.0000490

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2022

The c.3655G>T (p.V1219L) alteration is located in exon 18 (coding exon 18) of the PXDN gene. This alteration results from a G to T substitution at nucleotide position 3655, causing the valine (V) at amino acid position 1219 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Anterior segment dysgenesis 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 06, 2023

ClinVar contains an entry for this variant (Variation ID: 567848). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PXDN protein function. 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. This variant has not been reported in the literature in individuals affected with PXDN-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1219 of the PXDN protein (p.Val1219Leu). This variant is present in population databases (rs372395551, gnomAD 0.06%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.49

DEOGEN2

Benign

0.025

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.0038

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.54

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.99

REVEL

Benign

0.12

Sift

Benign

0.93

Sift4G

Benign

0.77

Polyphen

0.012

Vest4

0.62

MutPred

0.74

Loss of loop (P = 0.2237);

MVP

0.65

MPC

0.78

ClinPred

0.20

GERP RS

5.5

Varity_R

0.15

gMVP

0.73

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

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