Variant X-129746609-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003399.6(XPNPEP2):c.418A>G(p.Ile140Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000051 in 1,177,270 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000012 ( 0 hom., 0 hem., cov: 20)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

XPNPEP2
NM_003399.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10297024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPNPEP2	NM_003399.6 linkuse as main transcript	c.418A>G	p.Ile140Val	missense_variant	6/21	ENST00000371106.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
XPNPEP2	ENST00000371106.4 linkuse as main transcript	c.418A>G	p.Ile140Val	missense_variant	6/21	1	NM_003399.6	P1
XPNPEP2	ENST00000371105.7 linkuse as main transcript	n.658A>G		non_coding_transcript_exon_variant	6/6	2
XPNPEP2	ENST00000681234.1 linkuse as main transcript	n.683A>G		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes

AF:

0.0000119

AC:

AN:

84136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22126

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000126

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182979

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67493

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000726

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000457

AC:

AN:

1093134

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000119

AC:

AN:

84136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22126

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000126

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

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

Jan 03, 2024

The c.418A>G (p.I140V) alteration is located in exon 6 (coding exon 6) of the XPNPEP2 gene. This alteration results from a A to G substitution at nucleotide position 418, causing the isoleucine (I) at amino acid position 140 to be replaced by a valine (V). 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

0.061

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.010

T;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.2

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.15

Sift

Benign

0.43

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.36

.;B

Vest4

0.091

MutPred

0.51

Loss of catalytic residue at L145 (P = 0.0621);Loss of catalytic residue at L145 (P = 0.0621);

MVP

0.16

MPC

0.054

ClinPred

0.15

GERP RS

4.4

Varity_R

0.090

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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