rs794728007
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_000285.4(PEPD):c.692_694del(p.Tyr231del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,589,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y231Y) has been classified as Likely benign.
Frequency
Consequence
NM_000285.4 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEPD | NM_000285.4 | c.692_694del | p.Tyr231del | inframe_deletion | 10/15 | ENST00000244137.12 | |
PEPD | NM_001166056.2 | c.569_571del | p.Tyr190del | inframe_deletion | 8/13 | ||
PEPD | NM_001166057.2 | c.500_502del | p.Tyr167del | inframe_deletion | 8/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEPD | ENST00000244137.12 | c.692_694del | p.Tyr231del | inframe_deletion | 10/15 | 1 | NM_000285.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152218Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000163 AC: 34AN: 208060Hom.: 0 AF XY: 0.000151 AC XY: 17AN XY: 112546
GnomAD4 exome AF: 0.000188 AC: 270AN: 1436872Hom.: 0 AF XY: 0.000166 AC XY: 118AN XY: 712412
GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152336Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10AN XY: 74484
ClinVar
Submissions by phenotype
Prolidase deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PEPD c.692_694delACT (p.Tyr231del) variant is reported in one study in which it is found in two unrelated Portuguese individuals with prolidase deficiency in a homozygous state (Lupi et al. 2004). Control data are unavailable for this variant which is reported at a frequency of 0.00044 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cultured fibroblasts from these two individuals showed significantly decreased prolidase enzyme expression and activity compared to control fibroblasts (Lupi et al. 2004; Besio et al. 2013). Besio et al. (2013) demonstrated the variant resulted in reduced thermal stability, low catalytic efficiency and impaired Mn(II) cofactor binding of PEPD. Based on the evidence, the p.Tyr231del variant is classified as likely pathogenic for prolidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 20, 2021 | ACMG classification criteria: PS3 supporting, PS4 supporting, PM2, PM3, PM4 - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This variant, c.692_694del, results in the deletion of 1 amino acid(s) of the PEPD protein (p.Tyr231del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745834191, gnomAD 0.03%). This variant has been observed in individual(s) with prolidase deficiency (PMID: 15309682, 33877262). ClinVar contains an entry for this variant (Variation ID: 328810). 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: 23516557). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at