chrX-129742138-A-C

Variant names:

• chrX-129742138-A-C
• rs772460095
• NM_003399.6:c.80A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003399.6(XPNPEP2):​c.80A>C​(p.Asp27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,207,237 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: XPNPEP2 NM_003399.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0270
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 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.80A>C	p.Asp27Ala	missense	Exon 2 of 21	NP_003390.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPNPEP2	ENST00000371106.4	TSL:1 MANE Select	c.80A>C	p.Asp27Ala	missense	Exon 2 of 21	ENSP00000360147.3	O43895
	XPNPEP2	ENST00000880532.1		c.128A>C	p.Asp43Ala	missense	Exon 2 of 21	ENSP00000550591.1
	XPNPEP2	ENST00000880530.1		c.80A>C	p.Asp27Ala	missense	Exon 2 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes AF: 0.00000906 AC: 1 AN: 110398 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

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

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096839 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 2 AN XY: 362309

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26364

American (AMR) AF: 0.000114 AC: 4 AN: 35139

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30132

South Asian (SAS) AF: 0.00 AC: 0 AN: 54061

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841213

Other (OTH) AF: 0.0000217 AC: 1 AN: 46015

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000906 AC: 1 AN: 110398 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32682

African (AFR) AF: 0.00 AC: 0 AN: 30251

American (AMR) AF: 0.0000951 AC: 1 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3455

South Asian (SAS) AF: 0.00 AC: 0 AN: 2587

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52643

Other (OTH) AF: 0.00 AC: 0 AN: 1481

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.43
DANN	Benign	0.85
DEOGEN2	Benign	0.0089	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.58	N
PhyloP100		-0.027
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.024
Sift	Benign	0.37	T
Sift4G	Benign	0.71	T
Polyphen		0.013	B
Vest4		0.19
MutPred		0.29		Loss of disorder (P = 0.0977)
MVP		0.061
MPC		0.065
ClinPred		0.052	T
GERP RS		-1.8
Varity_R		0.062
gMVP		0.45
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772460095; hg19: chrX-128876114;