Genetic Variant PXDNL:c.3693-15_3693-14dupTT (chr8-51372094-C-CAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_144651.5(PXDNL):c.3693-15_3693-14dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,179,802 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 0)

Exomes 𝑓: 0.025 ( 3 hom. )

Consequence

PXDNL
NM_144651.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.286

Publications

1 publications found

Variant links:

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]

PXDNL links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDNL	NM_144651.5 link	c.3693-15_3693-14dupTT		intron_variant	Intron 18 of 22	ENST00000356297.5	NP_653252.4	A1KZ92-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PXDNL	ENST00000356297.5 link	c.3693-15_3693-14dupTT	intron_variant	Intron 18 of 22	1	NM_144651.5	ENSP00000348645.4	A1KZ92-1
PXDNL	ENST00000522933.5 link	c.912-15_912-14dupTT	intron_variant	Intron 1 of 5	5		ENSP00000428114.1	H0YAV0
PXDNL	ENST00000522628.5 link	n.1491-15_1491-14dupTT	intron_variant	Intron 2 of 4	2		ENSP00000429855.1	K4DIA6

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

266

AN:

148832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00169

Gnomad FIN

AF:

0.000404

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000237

Gnomad OTH

AF:

0.000979

GnomAD2 exomes

AF:

0.0296

AC:

3098

AN:

104804

AF XY:

0.0302

show subpopulations

Gnomad AFR exome

AF:

0.000381

Gnomad AMR exome

AF:

0.0615

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0245

AC:

25301

AN:

1030880

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

12291

AN XY:

509510

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00110

AC:

AN:

27280

American (AMR)

AF:

0.0533

AC:

1396

AN:

26180

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

376

AN:

19028

East Asian (EAS)

AF:

0.0134

AC:

368

AN:

27532

South Asian (SAS)

AF:

0.0185

AC:

1099

AN:

59316

European-Finnish (FIN)

AF:

0.0162

AC:

581

AN:

35860

Middle Eastern (MID)

AF:

0.00865

AC:

AN:

4394

European-Non Finnish (NFE)

AF:

0.0261

AC:

20534

AN:

786976

Other (OTH)

AF:

0.0198

AC:

879

AN:

44314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.254

Heterozygous variant carriers

3592

7185

10777

14370

17962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.00180

AC:

268

AN:

148922

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

150

AN XY:

72604

show subpopulations

African (AFR)

AF:

0.000723

AC:

AN:

40114

American (AMR)

AF:

0.0138

AC:

208

AN:

15034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.000198

AC:

AN:

5038

South Asian (SAS)

AF:

0.00169

AC:

AN:

4726

European-Finnish (FIN)

AF:

0.000404

AC:

AN:

9896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000237

AC:

AN:

67418

Other (OTH)

AF:

0.000970

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0486

Hom.:

1994

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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8-51372094-CA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over