rs6723697

Positions:

• chr2-1648187-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.3593G>A​(p.Arg1198Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,611,760 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (43 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.80

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=0.007972747).
• BP6: Variant 2-1648187-C-T is Benign according to our data. Variant chr2-1648187-C-T is described in ClinVar as [Benign]. Clinvar id is 471915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1648187-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1891/152236) while in subpopulation AFR AF= 0.043 (1786/41538). AF 95% confidence interval is 0.0413. There are 39 homozygotes in gnomad4. There are 886 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXDN	NM_012293.3	c.3593G>A	p.Arg1198Gln	missense_variant	17/23	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXDN	ENST00000252804.9	c.3593G>A	p.Arg1198Gln	missense_variant	17/23	1	NM_012293.3	ENSP00000252804	P1
PXDN	ENST00000478155.5	n.2697-3435G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1886 AN: 152118 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00331 AC: 816 AN: 246852 Hom.: 18 AF XY: 0.00251 AC XY: 336 AN XY: 134100

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000992

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00136 AC: 1980 AN: 1459524 Hom.: 43 Cov.: 31 AF XY: 0.00114 AC XY: 824 AN XY: 725584

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000604

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.0124 AC: 1891 AN: 152236 Hom.: 39 Cov.: 33 AF XY: 0.0119 AC XY: 886 AN XY: 74434

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00250 Hom.: 11

Bravo AF: 0.0143

ESP6500AA AF: 0.0426 AC: 170

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00370 AC: 447

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2020	- -

Anterior segment dysgenesis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.78
MPC		1.3
ClinPred		0.023	T
GERP RS		5.5
Varity_R		0.86
gMVP		0.85

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: rs6723697; hg19: chr2-1651959;