rs757386104
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000285.4(PEPD):c.1359_1361del(p.Glu453del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PEPD
NM_000285.4 inframe_deletion
NM_000285.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.36
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_000285.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEPD | NM_000285.4 | c.1359_1361del | p.Glu453del | inframe_deletion | 15/15 | ENST00000244137.12 | |
PEPD | NM_001166056.2 | c.1236_1238del | p.Glu412del | inframe_deletion | 13/13 | ||
PEPD | NM_001166057.2 | c.1167_1169del | p.Glu389del | inframe_deletion | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEPD | ENST00000244137.12 | c.1359_1361del | p.Glu453del | inframe_deletion | 15/15 | 1 | NM_000285.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248592Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134992
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461414Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727002
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Prolidase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1996 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 10, 2022 | This variant, c.1359_1361del, results in the deletion of 1 amino acid(s) of the PEPD protein (p.Glu453del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757386104, gnomAD 0.008%). This variant has been observed in individual(s) with clinical features of prolidase deficiency (PMID: 8198124). ClinVar contains an entry for this variant (Variation ID: 214). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PEPD function (PMID: 8900231). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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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