12-7189979-AG-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The ENST00000420616.6(PEX5):c.-252del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,499,380 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 1 hom. )
Consequence
PEX5
ENST00000420616.6 5_prime_UTR
ENST00000420616.6 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.99
Genes affected
PEX5 (HGNC:9719): (peroxisomal biogenesis factor 5) The product of this gene binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of neonatal adrenoleukodystrophy (NALD), a cause of Zellweger syndrome (ZWS) as well as may be a cause of infantile Refsum disease (IRD). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/152288) while in subpopulation EAS AF= 0.00213 (11/5174). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PEX5 | NM_001351132.2 | c.-17+231del | intron_variant | ENST00000675855.1 | NP_001338061.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PEX5 | ENST00000675855.1 | c.-17+231del | intron_variant | NM_001351132.2 | ENSP00000502374 | A1 |
Frequencies
GnomAD3 genomes 0.000138 AC: 21AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000126 AC: 12AN: 95500Hom.: 0 AF XY: 0.000113 AC XY: 6AN XY: 53104
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GnomAD4 exome AF: 0.0000490 AC: 66AN: 1347092Hom.: 1 Cov.: 31 AF XY: 0.0000361 AC XY: 24AN XY: 664434
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GnomAD4 genome 0.000138 AC: 21AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74466
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
PEX5-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 30, 2024 | The PEX5 c.47+1delG variant is predicted to result in an in-frame deletion (GT Donor). This variant is predicted to abolish a canonical splice donor site in some transcripts of the PEX5 gene (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge this variant has not been reported in the literature. In the gnomAD database, this variant has been reported in 17 heterozygous individuals of unknown phenotype; however, gnomAD warns that allele frequencies for this variant may not be reliable. Other pathogenic early termination variants documented in this gene are all downstream of this change, and in a majority of PEX5 transcripts, including the one documented in the Human Gene Mutation Database, this alteration is upstream of the coding region for this gene (NM_001131025.1:c.-252delG). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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