rs61747868

Positions:

• chr2-1638964-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.4088G>A​(p.Gly1363Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,980 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.148

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=0.003169328).
• BP6: Variant 2-1638964-C-T is Benign according to our data. Variant chr2-1638964-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1638964-C-T is described in Lovd as [Benign]. Variant chr2-1638964-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00726 (1106/152312) while in subpopulation AFR AF= 0.0244 (1016/41562). AF 95% confidence interval is 0.0232. There are 14 homozygotes in gnomad4. There are 532 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXDN	NM_012293.3	c.4088G>A	p.Gly1363Glu	missense_variant	21/23	ENST00000252804.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXDN	ENST00000252804.9	c.4088G>A	p.Gly1363Glu	missense_variant	21/23	1	NM_012293.3	P1
PXDN	ENST00000478155.5	n.3176G>A		non_coding_transcript_exon_variant	13/15	2
PXDN	ENST00000453308.1	c.225+338G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1100 AN: 152194 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00215 AC: 536 AN: 249244 Hom.: 5 AF XY: 0.00173 AC XY: 234 AN XY: 135222

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.00106 AC: 1550 AN: 1461668 Hom.: 15 Cov.: 35 AF XY: 0.000983 AC XY: 715 AN XY: 727124

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00726 AC: 1106 AN: 152312 Hom.: 14 Cov.: 33 AF XY: 0.00714 AC XY: 532 AN XY: 74482

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00156 Hom.: 2

Bravo AF: 0.00836

ESP6500AA AF: 0.0225 AC: 96

ESP6500EA AF: 0.000589 AC: 5

ExAC AF: 0.00274 AC: 332

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2023	See Variant Classification Assertion Criteria. -

Anterior segment dysgenesis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.4
DANN	Benign	0.19
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.12
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.018	B
Vest4		0.22
MVP		0.17
MPC		0.53
ClinPred		0.0069	T
GERP RS		3.2
Varity_R		0.038
gMVP		0.23

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: rs61747868; hg19: chr2-1642736;