rs61752102
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_000286.3(PEX12):βc.533_535delβ(p.Gln178del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000033 ( 0 hom., cov: 32)
Exomes π: 0.0000089 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PEX12
NM_000286.3 inframe_deletion
NM_000286.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.29
Genes affected
PEX12 (HGNC:8854): (peroxisomal biogenesis factor 12) This gene belongs to the peroxin-12 family. 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 Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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_000286.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
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Variant 17-35577182-AGTT-A is Pathogenic according to our data. Variant chr17-35577182-AGTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35577182-AGTT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX12 | NM_000286.3 | c.533_535del | p.Gln178del | inframe_deletion | 2/3 | ENST00000225873.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX12 | ENST00000225873.9 | c.533_535del | p.Gln178del | inframe_deletion | 2/3 | 1 | NM_000286.3 | P1 | |
PEX12 | ENST00000586663.2 | c.533_535del | p.Gln178del | inframe_deletion | 2/3 | 1 | |||
PEX12 | ENST00000585380.1 | c.533_535del | p.Gln178del | inframe_deletion | 3/3 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251488Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135914
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000889 AC: 13AN: 1461892Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727248
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74416
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2023 | Variant summary: PEX12 c.533_535delAAC (p.Gln178del) results in an in-frame deletion that is predicted to remove 1 amino acids from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251488 control chromosomes. c.533_535delAAC has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Alshenaifi_2019, Yik_2009, Steinberg_2004, Ebberink_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30561787, 21031596, 15542397, 19105186). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
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