Genetic Variant PXDN:p.Val941Met (chr2-1648959-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_012293.3(PXDN):c.2821G>A(p.Val941Met) variant causes a missense change. The variant allele was found at a frequency of 0.00404 in 1,607,360 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 18 hom. )

Consequence

PXDN
NM_012293.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.91

Publications

3 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009365916).

BP6

Variant 2-1648959-C-T is Benign according to our data. Variant chr2-1648959-C-T is described in ClinVar as Benign. ClinVar VariationId is 471913.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00347 (528/152146) while in subpopulation NFE AF = 0.00505 (343/67980). AF 95% confidence interval is 0.00461. There are 3 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDN	NM_012293.3 link	c.2821G>A	p.Val941Met	missense_variant	Exon 17 of 23	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PXDN	ENST00000252804.9 link	c.2821G>A	p.Val941Met	missense_variant	Exon 17 of 23	1	NM_012293.3	ENSP00000252804.4
PXDN	ENST00000478155.5 link	n.2697-4207G>A		intron_variant	Intron 9 of 14	2

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

528

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00505

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00352

AC:

829

AN:

235778

AF XY:

0.00349

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00489

Gnomad OTH exome

AF:

0.00312

GnomAD4 exome

AF:

0.00410

AC:

5966

AN:

1455214

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

2816

AN XY:

723238

show subpopulations

African (AFR)

AF:

0.000899

AC:

AN:

33354

American (AMR)

AF:

0.000517

AC:

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00105

AC:

AN:

85968

European-Finnish (FIN)

AF:

0.0112

AC:

569

AN:

50998

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00459

AC:

5096

AN:

1109080

Other (OTH)

AF:

0.00250

AC:

150

AN:

60046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

420

840

1261

1681

2101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<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:

0.00347

AC:

528

AN:

152146

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

260

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

41522

American (AMR)

AF:

0.000850

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0132

AC:

140

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00505

AC:

343

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00292

Hom.:

Bravo

AF:

0.00260

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000788

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00359

AC:

425

EpiCase

AF:

0.00344

EpiControl

AF:

0.00297

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 7

Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.6

PhyloP100

5.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.75

REVEL

Benign

0.14

Sift

Benign

0.22

Sift4G

Benign

0.19

Polyphen

0.64

Vest4

0.51

MVP

0.71

MPC

0.70

ClinPred

0.011

GERP RS

4.7

Varity_R

0.12

gMVP

0.56

Mutation Taster

=92/8

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over