Genetic Variant NM_000285.4:c.1463C>A (chr19-33387363-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000285.4(PEPD):c.1463C>A(p.Pro488His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P488R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27

Publications

0 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

PEPD links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37569118).

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	UniProt
PEPD	NM_000285.4	MANE Select	c.1463C>A	p.Pro488His	missense	Exon 15 of 15	NP_000276.2	A0A140VJR2
PEPD	NM_001166056.2		c.1340C>A	p.Pro447His	missense	Exon 13 of 13	NP_001159528.1	P12955-2
PEPD	NM_001166057.2		c.1271C>A	p.Pro424His	missense	Exon 13 of 13	NP_001159529.1	P12955-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEPD	ENST00000244137.12	TSL:1 MANE Select	c.1463C>A	p.Pro488His	missense	Exon 15 of 15	ENSP00000244137.5	P12955-1
PEPD	ENST00000651901.2		c.1553C>A	p.Pro518His	missense	Exon 16 of 16	ENSP00000498922.2	A0A494C165
PEPD	ENST00000588328.7	TSL:3	c.1529C>A	p.Pro510His	missense	Exon 16 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

M_CAP

Benign

0.074

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.060

MutationAssessor

Uncertain

2.2

PhyloP100

1.3

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.41

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.96

Vest4

0.27

MutPred

0.44

Loss of loop (P = 0.0153)

MVP

0.92

MPC

0.45

ClinPred

0.79

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

Mutation Taster

=66/34

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over