rs930569592

Variant names:

• chr2-1662066-G-A
• rs930569592
• NM_012293.3:c.1680+6C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-1662066-G-A
• chr2-1662066-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_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

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 Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. 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	c.1680+6C>T		splice_region_variant, intron_variant	Intron 13 of 22	ENST00000252804.9	NP_036425.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152096 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.0000203 AC: 4 AN: 196922 Hom.: 0 AF XY: 0.0000283 AC XY: 3 AN XY: 106124

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000224 AC: 32 AN: 1427852 Hom.: 0 Cov.: 31 AF XY: 0.0000226 AC XY: 16 AN XY: 707060

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.0000525

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000237

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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
DANN	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs930569592; hg19: chr2-1665838;