8-51339745-T-G

Variant names:

• chr8-51339745-T-G
• rs141860007
• NM_144651.5:c.4025A>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:3
• Conservation: PhyloP100: 0.326
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144651.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDNL	NM_144651.5	MANE Select	c.4025A>C	p.Asp1342Ala	missense	Exon 21 of 23	NP_653252.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDNL	ENST00000356297.5	TSL:1 MANE Select	c.4025A>C	p.Asp1342Ala	missense	Exon 21 of 23	ENSP00000348645.4	A1KZ92-1
	PXDNL	ENST00000894552.1		c.4205A>C	p.Asp1402Ala	missense	Exon 22 of 24	ENSP00000564611.1
	PXDNL	ENST00000894549.1		c.3953A>C	p.Asp1318Ala	missense	Exon 20 of 22	ENSP00000564608.1

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

GnomAD2 exomes AF: 0.00213 AC: 492 AN: 230796 AF XY: 0.00159

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 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

African (AFR) AF: 0.0261 AC: 847 AN: 32472

American (AMR) AF: 0.00184 AC: 73 AN: 39692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25356

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5690

European-Non Finnish (NFE) AF: 0.0000651 AC: 72 AN: 1105578

Other (OTH) AF: 0.00191 AC: 114 AN: 59706

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

African (AFR) AF: 0.0285 AC: 1184 AN: 41576

American (AMR) AF: 0.00255 AC: 39 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00326 Hom.: 16

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	PXDNL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.33
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs141860007; hg19: chr8-52252305;