NM_003399.6:c.712C>A

Variant names:

• chrX-129750542-C-A
• rs1316035895
• NM_003399.6:c.712C>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.712C>A​(p.Leu238Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000101 in 1,188,487 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000074 (0 hom. 2 hem.)
• Consequence: XPNPEP2 NM_003399.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3720213).
• BS2: High Hemizygotes in GnomAd4 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.712C>A	p.Leu238Ile	missense	Exon 8 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.712C>A	p.Leu238Ile	missense	Exon 8 of 21	ENSP00000360147.3	O43895
	XPNPEP2	ENST00000880532.1		c.760C>A	p.Leu254Ile	missense	Exon 8 of 21	ENSP00000550591.1
	XPNPEP2	ENST00000880530.1		c.712C>A	p.Leu238Ile	missense	Exon 8 of 21	ENSP00000550589.1

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112381 Hom.: 0 Cov.: 24

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: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000692 AC: 1 AN: 144579 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000743 AC: 8 AN: 1076106 Hom.: 0 Cov.: 30 AF XY: 0.00000573 AC XY: 2 AN XY: 349292

African (AFR) AF: 0.00 AC: 0 AN: 26168

American (AMR) AF: 0.00 AC: 0 AN: 31820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18973

East Asian (EAS) AF: 0.00 AC: 0 AN: 29562

South Asian (SAS) AF: 0.00 AC: 0 AN: 51123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38753

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3082

European-Non Finnish (NFE) AF: 0.00000962 AC: 8 AN: 831337

Other (OTH) AF: 0.00 AC: 0 AN: 45288

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112381 Hom.: 0 Cov.: 24 AF XY: 0.0000579 AC XY: 2 AN XY: 34517

African (AFR) AF: 0.00 AC: 0 AN: 30879

American (AMR) AF: 0.00 AC: 0 AN: 10674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53282

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

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	0.10
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.18
Sift	Benign	0.10	T
Sift4G	Benign	0.41	T
Polyphen		0.99	D
Vest4		0.44
MutPred		0.46		Loss of phosphorylation at T235 (P = 0.1464)
MVP		0.21
MPC		0.063
ClinPred		0.34	T
GERP RS		5.1
Varity_R		0.32
gMVP		0.52
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs1316035895; hg19: chrX-128884518;