rs17570

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000285.4(PEPD):c.1303C>T(p.Leu435Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,594,290 control chromosomes in the GnomAD database, including 55,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7715 hom., cov: 34)

Exomes 𝑓: 0.25 ( 47495 hom. )

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.70

Variant links:

Genes affected

PEPD (HGNC:8840): (peptidase D) This gene encodes a member of the peptidase family. The protein forms a homodimer that hydrolyzes dipeptides or tripeptides with C-terminal proline or hydroxyproline residues. The enzyme serves an important role in the recycling of proline, and may be rate limiting for the production of collagen. Mutations in this gene result in prolidase deficiency, which is characterized by the excretion of large amount of di- and tri-peptides containing proline. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

PEPD links:

PEPD (HGNC:):

PEPD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.922087E-4).

BP6

Variant 19-33387931-G-A is Benign according to our data. Variant chr19-33387931-G-A is described in ClinVar as [Benign]. Clinvar id is 328791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33387931-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEPD	NM_000285.4 linkuse as main transcript	c.1303C>T	p.Leu435Phe	missense_variant	14/15	ENST00000244137.12	NP_000276.2	P12955-1A0A140VJR2
PEPD	NM_001166056.2 linkuse as main transcript	c.1180C>T	p.Leu394Phe	missense_variant	12/13		NP_001159528.1	P12955-2
PEPD	NM_001166057.2 linkuse as main transcript	c.1111C>T	p.Leu371Phe	missense_variant	12/13		NP_001159529.1	P12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 linkuse as main transcript	c.1303C>T	p.Leu435Phe	missense_variant	14/15	1	NM_000285.4	ENSP00000244137.5		P12955-1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45870

AN:

152108

Hom.:

7707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.272

GnomAD3 exomes

AF:

0.229

AC:

48307

AN:

211038

Hom.:

5974

AF XY:

0.225

AC XY:

25869

AN XY:

115214

show subpopulations

Gnomad AFR exome

AF:

0.457

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.188

Gnomad SAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.243

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.252

AC:

362971

AN:

1442064

Hom.:

47495

Cov.:

AF XY:

0.248

AC XY:

177537

AN XY:

715260

show subpopulations

Gnomad4 AFR exome

AF:

0.482

Gnomad4 AMR exome

AF:

0.173

Gnomad4 ASJ exome

AF:

0.283

Gnomad4 EAS exome

AF:

0.172

Gnomad4 SAS exome

AF:

0.153

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.250

GnomAD4 genome

AF:

0.302

AC:

45911

AN:

152226

Hom.:

7715

Cov.:

AF XY:

0.296

AC XY:

22024

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.461

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.284

Gnomad4 EAS

AF:

0.196

Gnomad4 SAS

AF:

0.154

Gnomad4 FIN

AF:

0.254

Gnomad4 NFE

AF:

0.255

Gnomad4 OTH

AF:

0.270

Alfa

AF:

0.258

Hom.:

7519

Bravo

AF:

0.309

TwinsUK

AF:

0.262

AC:

971

ALSPAC

AF:

0.254

AC:

980

ESP6500AA

AF:

0.397

AC:

1543

ESP6500EA

AF:

0.240

AC:

1977

ExAC

AF:

0.213

AC:

25299

Asia WGS

AF:

0.192

AC:

670

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2015	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:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Prolidase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.35

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.079

T;T;T

MetaRNN

Benign

0.00099

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.96

L;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.84

T;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.046

MPC

0.12

ClinPred

0.011

GERP RS

3.4

Varity_R

0.27

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over