Genetic Variant NM_000285.4:c.634G>A (chr19-33463032-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_000285.4(PEPD):c.634G>A(p.Ala212Thr) 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. 13/21 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. A212P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.58

Publications

3 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-33463032-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 209997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.31450185).

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.634G>A	p.Ala212Thr	missense	Exon 9 of 15	NP_000276.2	A0A140VJR2
PEPD	NM_001166057.2		c.442G>A	p.Ala148Thr	missense	Exon 7 of 13	NP_001159529.1	P12955-3
PEPD	NM_001166056.2		c.548+15014G>A		intron	N/A	NP_001159528.1	P12955-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEPD	ENST00000244137.12	TSL:1 MANE Select	c.634G>A	p.Ala212Thr	missense	Exon 9 of 15	ENSP00000244137.5	P12955-1
PEPD	ENST00000651901.2		c.634G>A	p.Ala212Thr	missense	Exon 9 of 16	ENSP00000498922.2	A0A494C165
PEPD	ENST00000588328.7	TSL:3	c.634G>A	p.Ala212Thr	missense	Exon 9 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.25

Eigen

Benign

-0.091

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.022

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.93

REVEL

Uncertain

0.32

Sift

Benign

0.61

Sift4G

Benign

0.51

Polyphen

0.0040

Vest4

0.39

MutPred

0.64

Loss of MoRF binding (P = 0.1294)

MVP

0.79

MPC

0.13

ClinPred

0.52

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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