Variant X-129742179-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003399.6(XPNPEP2):c.121C>G(p.Pro41Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000501 in 1,177,862 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 0.000053 ( 0 hom. 13 hem. )

Consequence

XPNPEP2
NM_003399.6 missense, splice_region

Scores

Splicing: ADA: 0.001275

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.26

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2453244).

BS2

High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPNPEP2	NM_003399.6 linkuse as main transcript	c.121C>G	p.Pro41Ala	missense_variant, splice_region_variant	2/21	ENST00000371106.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
XPNPEP2	ENST00000371106.4 linkuse as main transcript	c.121C>G	p.Pro41Ala	missense_variant, splice_region_variant	2/21	1	NM_003399.6	P1
XPNPEP2	ENST00000371105.7 linkuse as main transcript	n.361C>G		splice_region_variant, non_coding_transcript_exon_variant	2/6	2
XPNPEP2	ENST00000681234.1 linkuse as main transcript	n.386C>G		splice_region_variant, non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes

AF:

0.0000196

AC:

AN:

101845

Hom.:

Cov.:

AF XY:

0.0000398

AC XY:

AN XY:

25121

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000404

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000689

AC:

AN:

174109

Hom.:

AF XY:

0.0000489

AC XY:

AN XY:

61409

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000747

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000748

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000919

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000530

AC:

AN:

1076017

Hom.:

Cov.:

AF XY:

0.0000379

AC XY:

AN XY:

342705

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000286

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000378

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000631

Gnomad4 OTH exome

AF:

0.0000442

GnomAD4 genome

AF:

0.0000196

AC:

AN:

101845

Hom.:

Cov.:

AF XY:

0.0000398

AC XY:

AN XY:

25121

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000404

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.121C>G (p.P41A) alteration is located in exon 2 (coding exon 2) of the XPNPEP2 gene. This alteration results from a C to G substitution at nucleotide position 121, causing the proline (P) at amino acid position 41 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;T

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

0.65

D;N

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.033

D;T

Polyphen

0.98

.;D

Vest4

0.39

MutPred

0.41

Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);

MVP

0.048

MPC

0.057

ClinPred

0.15

GERP RS

4.3

Varity_R

0.12

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0013

dbscSNV1_RF

Benign

0.062

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over