rs2230062

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000285.4(PEPD):c.1163G>A(p.Arg388His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,548,190 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0043 ( 25 hom., cov: 34)

Exomes 𝑓: 0.0041 ( 192 hom. )

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.37

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

prolidase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

PEPD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003597349).

BP6

Variant 19-33388071-C-T is Benign according to our data. Variant chr19-33388071-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4 link	c.1163G>A	p.Arg388His	missense_variant	Exon 14 of 15	ENST00000244137.12	NP_000276.2	P12955-1A0A140VJR2
PEPD	NM_001166056.2 link	c.1040G>A	p.Arg347His	missense_variant	Exon 12 of 13		NP_001159528.1	P12955-2
PEPD	NM_001166057.2 link	c.971G>A	p.Arg324His	missense_variant	Exon 12 of 13		NP_001159529.1	P12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 link	c.1163G>A	p.Arg388His	missense_variant	Exon 14 of 15	1	NM_000285.4	ENSP00000244137.5		P12955-1

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

657

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0918

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.0101

AC:

1493

AN:

147188

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.000397

Gnomad AMR exome

AF:

0.000527

Gnomad ASJ exome

AF:

0.000474

Gnomad EAS exome

AF:

0.0994

Gnomad FIN exome

AF:

0.00384

Gnomad NFE exome

AF:

0.000354

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.00411

AC:

5738

AN:

1395882

Hom.:

192

Cov.:

AF XY:

0.00434

AC XY:

2990

AN XY:

688864

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

31744

American (AMR)

AF:

0.000419

AC:

AN:

35836

Ashkenazi Jewish (ASJ)

AF:

0.000755

AC:

AN:

25172

East Asian (EAS)

AF:

0.101

AC:

3648

AN:

35954

South Asian (SAS)

AF:

0.0145

AC:

1152

AN:

79386

European-Finnish (FIN)

AF:

0.00513

AC:

229

AN:

44636

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.000242

AC:

261

AN:

1079444

Other (OTH)

AF:

0.00660

AC:

383

AN:

58018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

349

697

1046

1394

1743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00432

AC:

658

AN:

152308

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

375

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41566

American (AMR)

AF:

0.000327

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0922

AC:

476

AN:

5162

South Asian (SAS)

AF:

0.0172

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68020

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00465

Hom.:

Bravo

AF:

0.00417

ESP6500AA

AF:

0.000759

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00481

AC:

482

Asia WGS

AF:

0.0480

AC:

166

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Prolidase deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain

0.45

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Pathogenic

3.6

H;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.78

MPC

0.59

ClinPred

0.072

GERP RS

5.5

Varity_R

0.82

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over