NM_012293.3:c.2568dupC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_012293.3(PXDN):c.2568dupC(p.Cys857LeufsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,510,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PXDN
NM_012293.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.770

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

anterior segment dysgenesis 7
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

PXDN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-1649211-A-AG is Pathogenic according to our data. Variant chr2-1649211-A-AG is described in CliVar as Pathogenic. Clinvar id is 3610735.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-1649211-A-AG is described in CliVar as Pathogenic. Clinvar id is 3610735.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-1649211-A-AG is described in CliVar as Pathogenic. Clinvar id is 3610735.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDN	NM_012293.3 link	c.2568dupC	p.Cys857LeufsTer10	frameshift_variant	Exon 17 of 23	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PXDN	ENST00000252804.9 link	c.2568dupC	p.Cys857LeufsTer10	frameshift_variant	Exon 17 of 23	1	NM_012293.3	ENSP00000252804.4	Q92626-1
PXDN	ENST00000478155.5 link	n.2696+4416dupC		intron_variant	Intron 9 of 14	2
PXDN	ENST00000465809.1 link	n.*153dupC		downstream_gene_variant		4
PXDN	ENST00000493779.1 link	n.*31dupC		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000684

AC:

AN:

146182

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

245358

AF XY:

0.0000150

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000154

AC:

AN:

1364394

Hom.:

Cov.:

AF XY:

0.0000191

AC XY:

AN XY:

679524

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:

30872

American (AMR)

AF:

0.00

AC:

AN:

42230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22358

East Asian (EAS)

AF:

0.00

AC:

AN:

29602

South Asian (SAS)

AF:

0.0000118

AC:

AN:

85020

European-Finnish (FIN)

AF:

0.0000644

AC:

AN:

46550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1048442

Other (OTH)

AF:

0.00

AC:

AN:

54036

⚠️ 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: 0.380

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000684

AC:

AN:

146182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40044

American (AMR)

AF:

0.00

AC:

AN:

14720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4480

South Asian (SAS)

AF:

0.00

AC:

AN:

4180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66402

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 7

Pathogenic:1

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Cys857Leufs*10) in the PXDN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PXDN are known to be pathogenic (PMID: 21907015, 24939590). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PXDN-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.77

Mutation Taster

=4/196

disease causing (fs/PTC)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over