rs141024159

Positions:

• chr8-51408678-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000356297.5(PXDNL):​c.2946C>T​(p.Ala982=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,600,496 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (11 hom., cov: 33)
  • Exomes 𝑓: 0.013 (156 hom.)
• Consequence: PXDNL ENST00000356297.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.725

Genes affected

PXDNL (HGNC:26359): (peroxidasin like) Predicted to enable heme binding activity and peroxidase activity. Predicted to be involved in hydrogen peroxide catabolic process. Predicted to be located in cytoplasm. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-51408678-G-A is Benign according to our data. Variant chr8-51408678-G-A is described in ClinVar as [Benign]. Clinvar id is 403355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.725 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1747/152272) while in subpopulation NFE AF= 0.0161 (1095/68010). AF 95% confidence interval is 0.0153. There are 11 homozygotes in gnomad4. There are 890 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXDNL	NM_144651.5	c.2946C>T	p.Ala982=	synonymous_variant	17/23	ENST00000356297.5	NP_653252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXDNL	ENST00000356297.5	c.2946C>T	p.Ala982=	synonymous_variant	17/23	1	NM_144651.5	ENSP00000348645	P1
PXDNL	ENST00000522933.5	c.303C>T	p.Ala101=	synonymous_variant	1/6	5		ENSP00000428114
PXDNL	ENST00000522628.5	c.744C>T	p.Ala248=	synonymous_variant, NMD_transcript_variant	1/5	2		ENSP00000429855

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1748 AN: 152154 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0120 AC: 2645 AN: 221266 Hom.: 23 AF XY: 0.0120 AC XY: 1440 AN XY: 119952

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00656

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00514

Gnomad FIN exome AF: 0.0293

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0130 AC: 18866 AN: 1448224 Hom.: 156 Cov.: 31 AF XY: 0.0130 AC XY: 9340 AN XY: 719268

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00560

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0115 AC: 1747 AN: 152272 Hom.: 11 Cov.: 33 AF XY: 0.0120 AC XY: 890 AN XY: 74442

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00895

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0136 Hom.: 4

Bravo AF: 0.00935

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, silent variant -

PXDNL-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.80
DANN	Benign	0.51

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: rs141024159; hg19: chr8-52321238;