Variant X-129751813-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003399.6(XPNPEP2):c.808G>C(p.Asp270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,208,332 control chromosomes in the GnomAD database, including 1 homozygotes. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., 15 hem., cov: 23)

Exomes 𝑓: 0.000061 ( 1 hom. 15 hem. )

Consequence

XPNPEP2
NM_003399.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.360

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008470356).

BS2

High Hemizygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPNPEP2	NM_003399.6 link	c.808G>C	p.Asp270His	missense_variant	9/21	ENST00000371106.4	NP_003390.4	O43895

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPNPEP2	ENST00000371106.4 link	c.808G>C	p.Asp270His	missense_variant	9/21	1	NM_003399.6	ENSP00000360147.3		O43895

Frequencies

GnomAD3 genomes

AF:

0.000510

AC:

AN:

111666

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

33834

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

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:

0.0000377

Gnomad OTH

AF:

0.000659

GnomAD3 exomes

AF:

0.000136

AC:

AN:

183314

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

67762

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000611

AC:

AN:

1096612

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

362040

show subpopulations

Gnomad4 AFR exome

AF:

0.00201

Gnomad4 AMR exome

AF:

0.0000852

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:

0.00000238

Gnomad4 OTH exome

AF:

0.000196

GnomAD4 genome

AF:

0.000510

AC:

AN:

111720

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

33898

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.000284

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000377

Gnomad4 OTH

AF:

0.000651

Alfa

AF:

0.0000904

Hom.:

Bravo

AF:

0.000593

ESP6500AA

AF:

0.00235

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

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

Oct 01, 2024

The c.808G>C (p.D270H) alteration is located in exon 9 (coding exon 9) of the XPNPEP2 gene. This alteration results from a G to C substitution at nucleotide position 808, causing the aspartic acid (D) at amino acid position 270 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.2

DANN

Benign

0.89

DEOGEN2

Benign

0.0086

FATHMM_MKL

Benign

0.060

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.061

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.13

REVEL

Benign

0.14

Sift

Benign

0.17

Sift4G

Benign

0.20

Polyphen

0.71

Vest4

0.24

MVP

0.22

MPC

0.063

ClinPred

0.011

GERP RS

-2.0

Varity_R

0.12

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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