2-1634302-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_012293.3(PXDN):c.4342G>A(p.Val1448Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,597,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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]

LOC124907723 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23236594).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000591 (9/152358) while in subpopulation SAS AF= 0.000621 (3/4832). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXDN	NM_012293.3	c.4342G>A	p.Val1448Met	missense_variant	23/23	ENST00000252804.9
LOC124907723	XR_007086188.1	n.272C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXDN	ENST00000252804.9	c.4342G>A	p.Val1448Met	missense_variant	23/23	1	NM_012293.3	P1
PXDN	ENST00000478155.5	n.3430G>A		non_coding_transcript_exon_variant	15/15	2
PXDN	ENST00000493654.1	n.1679G>A		non_coding_transcript_exon_variant	2/2	2
PXDN	ENST00000453308.1	c.*132G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000603 AC: 13 AN: 215730 Hom.: 0 AF XY: 0.0000600 AC XY: 7 AN XY: 116594

Gnomad AFR exome AF: 0.0000788

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000187

Gnomad SAS exome AF: 0.000226

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 78 AN: 1444990 Hom.: 0 Cov.: 30 AF XY: 0.0000502 AC XY: 36 AN XY: 716994

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000205

Gnomad4 SAS exome AF: 0.000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000380

Gnomad4 OTH exome AF: 0.0000836

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74508

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000912 AC: 11

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anterior segment dysgenesis 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2017

This sequence change replaces valine with methionine at codon 1448 of the PXDN protein (p.Val1448Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs577701184, ExAC 0.06%). This variant has not been reported in the literature in individuals with a PXDN-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on PXDN function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.39
Sift	Benign	0.083	T
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.42		Gain of disorder (P = 0.1404);
MVP		0.71
MPC		0.70
ClinPred		0.15	T
GERP RS		4.9
Varity_R		0.038
gMVP		0.83

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: rs577701184; hg19: chr2-1638074; COSMIC: COSV105870894;