Genetic Variant XPNPEP2:p.Pro198Leu (chrX-129747709-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003399.6(XPNPEP2):c.593C>T(p.Pro198Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 1,210,590 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., 7 hem., cov: 24)

Exomes 𝑓: 0.000038 ( 0 hom. 14 hem. )

Consequence

XPNPEP2
NM_003399.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0310

Publications

1 publications found

Variant links:

Genes affected

XPNPEP2 (HGNC:12823): (X-prolyl aminopeptidase 2) Aminopeptidase P is a hydrolase specific for N-terminal imido bonds, which are common to several collagen degradation products, neuropeptides, vasoactive peptides, and cytokines. Structurally, the enzyme is a member of the 'pita bread fold' family and occurs in mammalian tissues in both soluble and GPI-anchored membrane-bound forms. A membrane-bound and soluble form of this enzyme have been identified as products of two separate genes. [provided by RefSeq, Jul 2008]

XPNPEP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025859207).

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003399.6. 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
	XPNPEP2	NM_003399.6	MANE Select	c.593C>T	p.Pro198Leu	missense	Exon 7 of 21	NP_003390.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XPNPEP2	ENST00000371106.4	TSL:1 MANE Select	c.593C>T	p.Pro198Leu	missense	Exon 7 of 21	ENSP00000360147.3	O43895
XPNPEP2	ENST00000880532.1		c.641C>T	p.Pro214Leu	missense	Exon 7 of 21	ENSP00000550591.1
XPNPEP2	ENST00000880530.1		c.593C>T	p.Pro198Leu	missense	Exon 7 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes

AF:

0.000294

AC:

AN:

112339

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000778

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000561

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.0000490

AC:

AN:

183512

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.000532

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000382

AC:

AN:

1098198

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

363560

show subpopulations

African (AFR)

AF:

0.000871

AC:

AN:

26399

American (AMR)

AF:

0.0000568

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4105

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

842135

Other (OTH)

AF:

0.000174

AC:

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000285

AC:

AN:

112392

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

34564

show subpopulations

African (AFR)

AF:

0.000744

AC:

AN:

30905

American (AMR)

AF:

0.000560

AC:

AN:

10715

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.000279

AC:

AN:

3585

South Asian (SAS)

AF:

0.00

AC:

AN:

2712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53207

Other (OTH)

AF:

0.00130

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000272

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.4

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.69

M_CAP

Benign

0.0093

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

PhyloP100

-0.031

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.076

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.12

Vest4

0.11

MVP

0.37

MPC

0.056

ClinPred

0.0082

GERP RS

2.0

Varity_R

0.11

gMVP

0.48

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over