X-129746664-C-T

Position:

• chrX-129746664-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003399.6(XPNPEP2):​c.473C>T​(p.Pro158Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: XPNPEP2 NM_003399.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.12

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPNPEP2	NM_003399.6	c.473C>T	p.Pro158Leu	missense_variant	6/21	ENST00000371106.4	NP_003390.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPNPEP2	ENST00000371106.4	c.473C>T	p.Pro158Leu	missense_variant	6/21	1	NM_003399.6	ENSP00000360147	P1
XPNPEP2	ENST00000371105.7	n.713C>T		non_coding_transcript_exon_variant	6/6	2
XPNPEP2	ENST00000681234.1	n.738C>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.473C>T (p.P158L) alteration is located in exon 6 (coding exon 6) of the XPNPEP2 gene. This alteration results from a C to T substitution at nucleotide position 473, causing the proline (P) at amino acid position 158 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.0	.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-9.3	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.88
MutPred		0.75		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.61
MPC		0.36
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs987480651; hg19: chrX-128880640;