8-51339745-T-G

Variant summary

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

The NM_144651.5(PXDNL):c.4025A>C(p.Asp1342Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,595,844 control chromosomes in the GnomAD database, including 27 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (15 hom.)
• Consequence: PXDNL NM_144651.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.326

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028561056).
• BP6: Variant 8-51339745-T-G is Benign according to our data. Variant chr8-51339745-T-G is described in ClinVar as [Benign]. Clinvar id is 792106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00818 (1246/152358) while in subpopulation AFR AF= 0.0285 (1184/41576). AF 95% confidence interval is 0.0271. There are 12 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXDNL	NM_144651.5	c.4025A>C	p.Asp1342Ala	missense_variant	21/23	ENST00000356297.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXDNL	ENST00000356297.5	c.4025A>C	p.Asp1342Ala	missense_variant	21/23	1	NM_144651.5	P1
PXDNL	ENST00000522933.5	c.1247A>C	p.Asp416Ala	missense_variant	4/6	5
PXDNL	ENST00000519183.1	n.441A>C		non_coding_transcript_exon_variant	1/3	3
PXDNL	ENST00000522628.5	c.1700-18848A>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1248 AN: 152240 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00213 AC: 492 AN: 230796 Hom.: 6 AF XY: 0.00159 AC XY: 199 AN XY: 125014

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000387

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.000774 AC: 1117 AN: 1443486 Hom.: 15 Cov.: 31 AF XY: 0.000691 AC XY: 495 AN XY: 716848

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000651

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00818 AC: 1246 AN: 152358 Hom.: 12 Cov.: 33 AF XY: 0.00800 AC XY: 596 AN XY: 74522

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00149 Hom.: 5

Bravo AF: 0.00909

ESP6500AA AF: 0.0257 AC: 93

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00224 AC: 270

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PXDNL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

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

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	11
Dann	Benign	0.20
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.031
Sift	Benign	0.55	T
Sift4G	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.26
MVP		0.30
MPC		0.14
ClinPred		0.0013	T
GERP RS		2.5
Varity_R		0.035
gMVP		0.078

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141860007; hg19: chr8-52252305;