rs930569592

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_012293.3(PXDN):c.1680+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,579,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

PXDN
NM_012293.3 splice_region, intron

Scores

Splicing: ADA: 0.00001391

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.591

Publications

0 publications found

Variant links:

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: G2P, PanelApp Australia, ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

PXDN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000394 (6/152096) while in subpopulation EAS AF = 0.000387 (2/5172). AF 95% confidence interval is 0.0000684. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDN	NM_012293.3 link	c.1680+6C>T		splice_region_variant, intron_variant	Intron 13 of 22	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PXDN	ENST00000252804.9 link	c.1680+6C>T	splice_region_variant, intron_variant	Intron 13 of 22	1	NM_012293.3	ENSP00000252804.4	Q92626-1
PXDN	ENST00000433670.5 link	c.1665+6C>T	splice_region_variant, intron_variant	Intron 13 of 15	1		ENSP00000402738.1	H7C1W1
PXDN	ENST00000425171.2 link	c.1608+6C>T	splice_region_variant, intron_variant	Intron 12 of 15	5		ENSP00000398363.2	C9J4I9
PXDN	ENST00000478155.5 link	n.2272+6C>T	splice_region_variant, intron_variant	Intron 6 of 14	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

196922

AF XY:

0.0000283

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000136

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000235

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000224

AC:

AN:

1427852

Hom.:

Cov.:

AF XY:

0.0000226

AC XY:

AN XY:

707060

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32860

American (AMR)

AF:

0.00

AC:

AN:

39660

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25492

East Asian (EAS)

AF:

0.0000525

AC:

AN:

38094

South Asian (SAS)

AF:

0.00

AC:

AN:

81448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.0000237

AC:

AN:

1095130

Other (OTH)

AF:

0.0000338

AC:

AN:

59110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 7

Uncertain:1

May 02, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with PXDN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 13 of the PXDN gene. It does not directly change the encoded amino acid sequence of the PXDN protein, but it affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.20

(source)

DANN

Benign

0.47

PhyloP100

-0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over