dbSNP rs267606944: PEPD:p.Glu412Lys (chr19-33388000-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000285.4(PEPD):c.1234G>A(p.Glu412Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.37

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity PEPD_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 19-33388000-C-T is Pathogenic according to our data. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-33388000-C-T is described in CliVar as Pathogenic. Clinvar id is 216.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4 link	c.1234G>A	p.Glu412Lys	missense_variant	Exon 14 of 15	ENST00000244137.12	NP_000276.2	P12955-1A0A140VJR2
PEPD	NM_001166056.2 link	c.1111G>A	p.Glu371Lys	missense_variant	Exon 12 of 13		NP_001159528.1	P12955-2
PEPD	NM_001166057.2 link	c.1042G>A	p.Glu348Lys	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.1234G>A	p.Glu412Lys	missense_variant	Exon 14 of 15	1	NM_000285.4	ENSP00000244137.5		P12955-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1426452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706130

African (AFR)

AF:

0.00

AC:

AN:

32948

American (AMR)

AF:

0.00

AC:

AN:

39304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25462

East Asian (EAS)

AF:

0.00

AC:

AN:

38240

South Asian (SAS)

AF:

0.00

AC:

AN:

81564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094622

Other (OTH)

AF:

0.00

AC:

AN:

59066

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Prolidase deficiency

Pathogenic:1

Dec 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

5.2

H;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.99

MutPred

0.97

Gain of methylation at E412 (P = 0.0029);.;.;

MVP

0.97

MPC

0.57

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

Mutation Taster

=3/97

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over