rs147190409

Variant names:

• chrX-129751813-G-C
• rs147190409
• NM_003399.6:c.808G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.360
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008470356).
• BS2: High Hemizygotes in GnomAd4 at 15 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.808G>C	p.Asp270His	missense	Exon 9 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.808G>C	p.Asp270His	missense	Exon 9 of 21	ENSP00000360147.3	O43895
	XPNPEP2	ENST00000880532.1		c.856G>C	p.Asp286His	missense	Exon 9 of 21	ENSP00000550591.1
	XPNPEP2	ENST00000880530.1		c.808G>C	p.Asp270His	missense	Exon 9 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes AF: 0.000510 AC: 57 AN: 111666 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000136 AC: 25 AN: 183314 AF XY: 0.0000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000611 AC: 67 AN: 1096612 Hom.: 1 Cov.: 30 AF XY: 0.0000414 AC XY: 15 AN XY: 362040

African (AFR) AF: 0.00201 AC: 53 AN: 26368

American (AMR) AF: 0.0000852 AC: 3 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840757

Other (OTH) AF: 0.000196 AC: 9 AN: 46030

GnomAD4 genome AF: 0.000510 AC: 57 AN: 111720 Hom.: 0 Cov.: 23 AF XY: 0.000443 AC XY: 15 AN XY: 33898

African (AFR) AF: 0.00166 AC: 51 AN: 30743

American (AMR) AF: 0.000284 AC: 3 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53086

Other (OTH) AF: 0.000651 AC: 1 AN: 1536

Alfa AF: 0.0000904 Hom.: 1

Bravo AF: 0.000593

ESP6500AA AF: 0.00235 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

ClinVar

ClinVar submissions as Germline

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	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.2
DANN	Benign	0.89
DEOGEN2	Benign	0.0086	T
FATHMM_MKL	Benign	0.060	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.36
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.71	P
Vest4		0.24
MVP		0.22
MPC		0.063
ClinPred		0.011	T
GERP RS		-2.0
Varity_R		0.12
gMVP		0.59
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs147190409; hg19: chrX-128885789;