rs147066927

Variant names:

• chr2-1643470-C-A
• rs147066927
• NM_012293.3:c.3850G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012293.3(PXDN):​c.3850G>T​(p.Val1284Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00777 in 1,613,996 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0079 (176 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.73
• Publications: 4 publications found

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]

PXDN Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009080559).
• BP6: Variant 2-1643470-C-A is Benign according to our data. Variant chr2-1643470-C-A is described in ClinVar as Benign. ClinVar VariationId is 260227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDN	NM_012293.3	MANE Select	c.3850G>T	p.Val1284Leu	missense	Exon 19 of 23	NP_036425.1	Q92626-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDN	ENST00000252804.9	TSL:1 MANE Select	c.3850G>T	p.Val1284Leu	missense	Exon 19 of 23	ENSP00000252804.4	Q92626-1
	PXDN	ENST00000857505.1		c.3778G>T	p.Val1260Leu	missense	Exon 18 of 22	ENSP00000527564.1
	PXDN	ENST00000453308.1	TSL:3	n.1G>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000414098.1	H7C3W2

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152190 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0452

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00542

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0114 AC: 2849 AN: 249298 AF XY: 0.0136

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00744

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.00701

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.00794 AC: 11611 AN: 1461688 Hom.: 176 Cov.: 34 AF XY: 0.00916 AC XY: 6664 AN XY: 727128

African (AFR) AF: 0.00218 AC: 73 AN: 33480

American (AMR) AF: 0.00780 AC: 349 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 640 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0442 AC: 3816 AN: 86258

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53380

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5768

European-Non Finnish (NFE) AF: 0.00512 AC: 5693 AN: 1111868

Other (OTH) AF: 0.0113 AC: 682 AN: 60374

GnomAD4 genome AF: 0.00605 AC: 922 AN: 152308 Hom.: 10 Cov.: 31 AF XY: 0.00687 AC XY: 512 AN XY: 74478

African (AFR) AF: 0.00111 AC: 46 AN: 41574

American (AMR) AF: 0.0116 AC: 177 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00542 AC: 369 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00724 Hom.: 5

Bravo AF: 0.00569

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00118 AC: 5

ESP6500EA AF: 0.00675 AC: 57

ExAC AF: 0.0118 AC: 1425

Asia WGS AF: 0.0180 AC: 67 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Anterior segment dysgenesis 7 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.068
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.055	T
Sift4G	Benign	0.078	T
Polyphen		0.24	B
Vest4		0.10
MutPred		0.50		Loss of catalytic residue at F1289 (P = 0.3761)
MPC		0.56
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.72
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs147066927; hg19: chr2-1647242; COSMIC: COSV53244501;