Genetic Variant NM_000285.4:c.1303C>A (chr19-33387931-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000285.4(PEPD):c.1303C>A(p.Leu435Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L435F) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.70

Publications

45 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.099193335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000285.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PEPD	NM_000285.4	MANE Select	c.1303C>A	p.Leu435Ile	missense	Exon 14 of 15	NP_000276.2
PEPD	NM_001166056.2		c.1180C>A	p.Leu394Ile	missense	Exon 12 of 13	NP_001159528.1
PEPD	NM_001166057.2		c.1111C>A	p.Leu371Ile	missense	Exon 12 of 13	NP_001159529.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PEPD	ENST00000244137.12	TSL:1 MANE Select	c.1303C>A	p.Leu435Ile	missense	Exon 14 of 15	ENSP00000244137.5
PEPD	ENST00000651901.2		c.1303C>A	p.Leu435Ile	missense	Exon 14 of 16	ENSP00000498922.2
PEPD	ENST00000588328.7	TSL:3	c.1369C>A	p.Leu457Ile	missense	Exon 15 of 16	ENSP00000468516.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715554

African (AFR)

AF:

0.00

AC:

AN:

33252

American (AMR)

AF:

0.00

AC:

AN:

41988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25768

East Asian (EAS)

AF:

0.00

AC:

AN:

38968

South Asian (SAS)

AF:

0.00

AC:

AN:

83310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103288

Other (OTH)

AF:

0.00

AC:

AN:

59646

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

10977

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.15

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.20

M_CAP

Benign

0.018

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.23

PhyloP100

2.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.030

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.13

MutPred

0.25

Gain of catalytic residue at L440 (P = 0.0698)

MVP

0.58

MPC

0.12

ClinPred

0.22

GERP RS

3.4

Varity_R

0.25

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over