rs121917725
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000285.4(PEPD):c.793C>T(p.Arg265Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
PEPD
NM_000285.4 stop_gained
NM_000285.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.25
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-33411697-G-A is Pathogenic according to our data. Variant chr19-33411697-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 215.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEPD | NM_000285.4 | c.793C>T | p.Arg265Ter | stop_gained | 11/15 | ENST00000244137.12 | |
PEPD | NM_001166056.2 | c.670C>T | p.Arg224Ter | stop_gained | 9/13 | ||
PEPD | NM_001166057.2 | c.601C>T | p.Arg201Ter | stop_gained | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEPD | ENST00000244137.12 | c.793C>T | p.Arg265Ter | stop_gained | 11/15 | 1 | NM_000285.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248524Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135068
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GnomAD4 exome AF: 0.00000824 AC: 12AN: 1457132Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 6AN XY: 725260
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Prolidase deficiency Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2006 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Arg265*) in the PEPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEPD are known to be pathogenic (PMID: 8198124, 10721675, 12384772, 17142620). This variant is present in population databases (rs121917725, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of prolidase deficiency (PMID: 16470701). ClinVar contains an entry for this variant (Variation ID: 215). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at