X-129746638-T-C

Variant names:

• chrX-129746638-T-C
• rs3747343
• NM_003399.6:c.447T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003399.6(XPNPEP2):​c.447T>C​(p.Pro149Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,205,591 control chromosomes in the GnomAD database, including 52,644 homozygotes. There are 128,535 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (10119 hom., 12653 hem., cov: 20)
  • Exomes 𝑓: 0.32 (42525 hom. 115882 hem.)
• Consequence: XPNPEP2 NM_003399.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.76

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-129746638-T-C is Benign according to our data. Variant chrX-129746638-T-C is described in ClinVar as [Benign]. Clinvar id is 380656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-129746638-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPNPEP2	NM_003399.6	c.447T>C	p.Pro149Pro	synonymous_variant	Exon 6 of 21	ENST00000371106.4	NP_003390.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPNPEP2	ENST00000371106.4	c.447T>C	p.Pro149Pro	synonymous_variant	Exon 6 of 21	1	NM_003399.6	ENSP00000360147.3
XPNPEP2	ENST00000371105.7	n.687T>C		non_coding_transcript_exon_variant	Exon 6 of 6	2
XPNPEP2	ENST00000681234.1	n.712T>C		non_coding_transcript_exon_variant	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.445 AC: 47915 AN: 107644 Hom.: 10114 Cov.: 20

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.384 AC: 70472 AN: 183329 AF XY: 0.370

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.318 AC: 348687 AN: 1097890 Hom.: 42525 Cov.: 32 AF XY: 0.319 AC XY: 115882 AN XY: 363380

Gnomad4 AFR exome AF: 0.814 AC: 21488 AN: 26389

Gnomad4 AMR exome AF: 0.366 AC: 12884 AN: 35196

Gnomad4 ASJ exome AF: 0.235 AC: 4548 AN: 19385

Gnomad4 EAS exome AF: 0.751 AC: 22680 AN: 30202

Gnomad4 SAS exome AF: 0.431 AC: 23305 AN: 54133

Gnomad4 FIN exome AF: 0.292 AC: 11816 AN: 40467

Gnomad4 NFE exome AF: 0.279 AC: 234876 AN: 841915

Gnomad4 Remaining exome AF: 0.345 AC: 15921 AN: 46086

GnomAD4 genome AF: 0.445 AC: 47973 AN: 107701 Hom.: 10119 Cov.: 20 AF XY: 0.419 AC XY: 12653 AN XY: 30219

Gnomad4 AFR AF: 0.792 AC: 0.791761 AN: 0.791761

Gnomad4 AMR AF: 0.360 AC: 0.359756 AN: 0.359756

Gnomad4 ASJ AF: 0.248 AC: 0.247794 AN: 0.247794

Gnomad4 EAS AF: 0.768 AC: 0.768377 AN: 0.768377

Gnomad4 SAS AF: 0.430 AC: 0.430316 AN: 0.430316

Gnomad4 FIN AF: 0.269 AC: 0.268599 AN: 0.268599

Gnomad4 NFE AF: 0.281 AC: 0.280857 AN: 0.280857

Gnomad4 OTH AF: 0.412 AC: 0.411924 AN: 0.411924

Alfa AF: 0.356 Hom.: 39811

Bravo AF: 0.476

EpiCase AF: 0.266

EpiControl AF: 0.276

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 15, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.53
DANN	Benign	0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Publications

LitVar

Other links and lift over

dbSNP: rs3747343; hg19: chrX-128880614; COSMIC: COSV64367834;