rs202132697

chr2-1648590-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012293.3(PXDN):c.3190G>A(p.Ala1064Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00239 in 1,609,374 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.77

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034437597).
• BP6: Variant 2-1648590-C-T is Benign according to our data. Variant chr2-1648590-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 217340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1648590-C-T is described in Lovd as [Likely_benign]. Variant chr2-1648590-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00167 (247/147952) while in subpopulation SAS AF= 0.00282 (13/4602). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXDN	NM_012293.3	c.3190G>A	p.Ala1064Thr	missense_variant	17/23	ENST00000252804.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXDN	ENST00000252804.9	c.3190G>A	p.Ala1064Thr	missense_variant	17/23	1	NM_012293.3	P1
PXDN	ENST00000478155.5	n.2697-3838G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 247 AN: 147820 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000300

Gnomad AMI AF: 0.00335

Gnomad AMR AF: 0.000538

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00282

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00183 AC: 455 AN: 248828 Hom.: 2 AF XY: 0.00179 AC XY: 242 AN XY: 134962

Gnomad AFR exome AF: 0.000321

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00262

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00247 AC: 3605 AN: 1461422 Hom.: 7 Cov.: 31 AF XY: 0.00251 AC XY: 1827 AN XY: 726974

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.00275

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00167 AC: 247 AN: 147952 Hom.: 0 Cov.: 33 AF XY: 0.00148 AC XY: 107 AN XY: 72218

Gnomad4 AFR AF: 0.000299

Gnomad4 AMR AF: 0.000538

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00282

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00270

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00146

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00189 AC: 230

EpiCase AF: 0.00213

EpiControl AF: 0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anterior segment dysgenesis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2021

- -

Developmental cataract Benign:1

Likely benign, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

PXDN-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.86	P
Vest4		0.56
MVP		0.85
MPC		1.0
ClinPred		0.052	T
GERP RS		5.7
Varity_R		0.30
gMVP		0.82

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

Other links and lift over

dbSNP: rs202132697; hg19: chr2-1652362;