rs760111651

Variant names:

• chrX-129746609-A-G
• rs760111651
• NM_003399.6:c.418A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-129746609-A-G
• chrX-129746609-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003399.6(XPNPEP2):​c.418A>G​(p.Ile140Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000051 in 1,177,270 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: XPNPEP2 NM_003399.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10297024).

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.418A>G	p.Ile140Val	missense	Exon 6 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.418A>G	p.Ile140Val	missense	Exon 6 of 21	ENSP00000360147.3	O43895
	XPNPEP2	ENST00000880532.1		c.466A>G	p.Ile156Val	missense	Exon 6 of 21	ENSP00000550591.1
	XPNPEP2	ENST00000880530.1		c.418A>G	p.Ile140Val	missense	Exon 6 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes AF: 0.0000119 AC: 1 AN: 84136 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000126

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

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 182979 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000726

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1093134 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 360752

African (AFR) AF: 0.00 AC: 0 AN: 26225

American (AMR) AF: 0.000143 AC: 5 AN: 34901

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19229

East Asian (EAS) AF: 0.00 AC: 0 AN: 29881

South Asian (SAS) AF: 0.00 AC: 0 AN: 53770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40239

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4079

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839003

Other (OTH) AF: 0.00 AC: 0 AN: 45807

GnomAD4 genome AF: 0.0000119 AC: 1 AN: 84136 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 22126

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

African (AFR) AF: 0.00 AC: 0 AN: 22004

American (AMR) AF: 0.000126 AC: 1 AN: 7931

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2001

East Asian (EAS) AF: 0.00 AC: 0 AN: 2680

South Asian (SAS) AF: 0.00 AC: 0 AN: 1927

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4815

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 153

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 40990

Other (OTH) AF: 0.00 AC: 0 AN: 1103

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.061
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.62
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.15
Sift	Benign	0.43	T
Sift4G	Benign	0.36	T
Polyphen		0.36	B
Vest4		0.091
MutPred		0.51		Loss of catalytic residue at L145 (P = 0.0621)
MVP		0.16
MPC		0.054
ClinPred		0.15	T
GERP RS		4.4
Varity_R		0.090
gMVP		0.49
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs760111651; hg19: chrX-128880585;