Genetic Variant NM_003399.6:c.659T>C (chrX-129750489-T-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_003399.6(XPNPEP2):c.659T>C(p.Val220Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000277 in 1,082,535 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.000028 ( 0 hom. 11 hem. )

Consequence

XPNPEP2
NM_003399.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.63

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

BS2

High Hemizygotes in GnomAdExome4 at 11 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.659T>C	p.Val220Ala	missense	Exon 8 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.659T>C	p.Val220Ala	missense	Exon 8 of 21	ENSP00000360147.3	O43895
XPNPEP2	ENST00000880532.1		c.707T>C	p.Val236Ala	missense	Exon 8 of 21	ENSP00000550591.1
XPNPEP2	ENST00000880530.1		c.659T>C	p.Val220Ala	missense	Exon 8 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000653

AC:

AN:

153097

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1082535

Hom.:

Cov.:

AF XY:

0.0000312

AC XY:

AN XY:

352741

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26281

American (AMR)

AF:

0.00

AC:

AN:

32827

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19062

East Asian (EAS)

AF:

0.00

AC:

AN:

29788

South Asian (SAS)

AF:

0.00

AC:

AN:

51548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39407

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3755

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

834291

Other (OTH)

AF:

0.00

AC:

AN:

45576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.00000833

AC:

ClinVar

ClinVar submissions as Germline

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

Uncertain

0.45

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.2

PhyloP100

6.6

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.71

MutPred

0.54

Loss of stability (P = 0.0591)

MVP

0.40

MPC

0.29

ClinPred

0.91

GERP RS

5.1

Varity_R

0.85

gMVP

0.83

Mutation Taster

=50/50

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over