rs61752107
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000286.3(PEX12):c.733_734insGCCT(p.Leu245CysfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 0 hom. )
Consequence
PEX12
NM_000286.3 frameshift
NM_000286.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.742
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-35576128-A-AAGGC is Pathogenic according to our data. Variant chr17-35576128-A-AAGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX12 | NM_000286.3 | c.733_734insGCCT | p.Leu245CysfsTer19 | frameshift_variant | 3/3 | ENST00000225873.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX12 | ENST00000225873.9 | c.733_734insGCCT | p.Leu245CysfsTer19 | frameshift_variant | 3/3 | 1 | NM_000286.3 | P1 | |
PEX12 | ENST00000586663.2 | c.733_734insGCCT | p.Leu245CysfsTer19 | frameshift_variant | 3/3 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249910Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135240
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GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58AN XY: 727224
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 05, 2017 | The PEX12 c.730_733dupGCCT (p.Leu245CysfsTer19) variant has been reported in two studies and identified in three patients in a compound heterozygous state and one patient in a heterozygous state, all with peroxisome biogenesis disorders, with three specifically noted to be in the Zellweger syndrome spectrum (Chang et al. 1997; Steinberg et al. 2004; Yik et al. 2009; Ebberink et al. 2011). All individuals with the variant in a compound heterozygous state had a second insertion variant. Control data are unavailable for the p.Leu245CysfsTer19 variant, but it is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. To evaluate the effect of PEX12 expression on peroxisomal protein import, Chang et al. (1997) used patient fibroblasts and noted that when the variant was present, cDNA expression was observed in the cytoplasm only; however, expression of PEX12 in these cells reversed the effect and import into the peroxisomes was observed. Based on the evidence and due to the potential impact of frameshift variants, the p.Leu245CysfsTer19 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 16, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 29, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Leu245Cysfs*19) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs61752107, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with peroxisome biogenesis disorders (PMID: 9090384, 19105186). This variant is also known as c.733_734insGCCT. ClinVar contains an entry for this variant (Variation ID: 371737). Studies have shown that this premature translational stop signal alters PEX12 gene expression (PMID: 9090384). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Leu297Thrfs*12) have been determined to be pathogenic (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2023 | Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost and replaced with 18 incorrect amino acids. Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9090384, 19105186, 21031596, 19877282, 15542397, 9792857, 29389947) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 17, 2018 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 02, 2018 | Variant summary: PEX12 c.730_733dupGCCT (p.Leu245CysfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory, c.888_889delCT (p.Leu297fsX12). The variant allele was found at a frequency of 1.6e-05 in 244662 control chromosomes (gnomAD). The variant, c.730_733dupGCCT has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorders (Chang_1998, Cordoba_2018, Ebberink_2010,Yik_2009). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Chang_1998). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder type 3B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 16, 2016 | - - |
PEX12-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshift variant is found in the last exon of PEX12 and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). Truncating variants located downstream of this alteration have been reported in individuals with PEX12-related disorders in the literature (PMID: 26094004). This variant, also referred to as c.733-734insGCCT and c.733-734insGCC (p.L245Cfsx19), has been previously reported as a compound heterozygous change in two individuals with peroxisome biogenesis disorder (PMID: 9090384, 9792857, 15542397, 29389947, 21031596). The c.730_733dup (p.Leu245CysfsTer19) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/249910) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.730_733dup (p.Leu245CysfsTer19) variant is classified as Pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at