rs377568487

Variant names:

• chrX-129752170-G-A
• rs377568487
• NM_003399.6:c.842G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003399.6(XPNPEP2):​c.842G>A​(p.Arg281His) variant causes a missense change. The variant allele was found at a frequency of 0.00000579 in 1,209,488 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: XPNPEP2 NM_003399.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30866176).
• 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.842G>A	p.Arg281His	missense	Exon 10 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.842G>A	p.Arg281His	missense	Exon 10 of 21	ENSP00000360147.3	O43895
	XPNPEP2	ENST00000880532.1		c.890G>A	p.Arg297His	missense	Exon 10 of 21	ENSP00000550591.1
	XPNPEP2	ENST00000880530.1		c.842G>A	p.Arg281His	missense	Exon 10 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111725 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 182270 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097763 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363143

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.0000853 AC: 3 AN: 35151

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.00 AC: 0 AN: 54059

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841875

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111725 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33903

African (AFR) AF: 0.00 AC: 0 AN: 30692

American (AMR) AF: 0.00 AC: 0 AN: 10511

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

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

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53137

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

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	0.10
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.9
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.022	D
Polyphen		0.98	D
Vest4		0.35
MVP		0.067
MPC		0.30
ClinPred		0.78	D
GERP RS		5.8
Varity_R		0.82
gMVP		0.65
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs377568487; hg19: chrX-128886146; COSMIC: COSV105921368;