rs61747875

Positions:

• chr2-1638928-G-A
• chr2-1638928-G-C

Variant summary

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

The ENST00000252804.9(PXDN):​c.4124C>T​(p.Thr1375Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,964 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1375P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0078 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: PXDN ENST00000252804.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.21

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=0.0029197633).
• BP6: Variant 2-1638928-G-A is Benign according to our data. Variant chr2-1638928-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1638928-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00783 (1192/152306) while in subpopulation AFR AF= 0.0263 (1091/41558). AF 95% confidence interval is 0.025. There are 18 homozygotes in gnomad4. There are 582 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXDN	NM_012293.3	c.4124C>T	p.Thr1375Ile	missense_variant	21/23	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXDN	ENST00000252804.9	c.4124C>T	p.Thr1375Ile	missense_variant	21/23	1	NM_012293.3	ENSP00000252804	P1
PXDN	ENST00000478155.5	n.3212C>T		non_coding_transcript_exon_variant	13/15	2
PXDN	ENST00000453308.1	c.225+374C>T		intron_variant, NMD_transcript_variant		3		ENSP00000414098

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1177 AN: 152188 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

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: 0.000470

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00227 AC: 567 AN: 249300 Hom.: 5 AF XY: 0.00180 AC XY: 244 AN XY: 135252

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00110 AC: 1613 AN: 1461658 Hom.: 17 Cov.: 35 AF XY: 0.00102 AC XY: 744 AN XY: 727114

Gnomad4 AFR exome AF: 0.0296

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00783 AC: 1192 AN: 152306 Hom.: 18 Cov.: 33 AF XY: 0.00782 AC XY: 582 AN XY: 74464

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00130 Hom.: 3

Bravo AF: 0.00895

ESP6500AA AF: 0.0241 AC: 103

ESP6500EA AF: 0.000589 AC: 5

ExAC AF: 0.00284 AC: 344

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Anterior segment dysgenesis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.0
DANN	Benign	0.79
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.088
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.018	B
Vest4		0.13
MVP		0.15
MPC		0.44
ClinPred		0.0041	T
GERP RS		3.0
Varity_R		0.030
gMVP		0.40

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: rs61747875; hg19: chr2-1642700;