rs61752104
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000286.3(PEX12):c.541_542insT(p.Tyr181LeufsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y181Y) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
PEX12
NM_000286.3 frameshift
NM_000286.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.49
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 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-35577176-T-TA is Pathogenic according to our data. Variant chr17-35577176-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 2201009.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PEX12 | NM_000286.3 | c.541_542insT | p.Tyr181LeufsTer37 | frameshift_variant | 2/3 | ENST00000225873.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PEX12 | ENST00000225873.9 | c.541_542insT | p.Tyr181LeufsTer37 | frameshift_variant | 2/3 | 1 | NM_000286.3 | P1 | |
| PEX12 | ENST00000586663.2 | c.541_542insT | p.Tyr181LeufsTer37 | frameshift_variant | 2/3 | 1 | |||
| PEX12 | ENST00000585380.1 | c.541_542insT | p.Tyr181LeufsTer37 | frameshift_variant | 3/3 | 4 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251490Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135916
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727246
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GnomAD4 genome 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Tyr181Leufs*37) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs61752104, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 19105186). This variant is also known as 542insT (Y181fs). ClinVar contains an entry for this variant (Variation ID: 2201009). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Gln349del) have been determined to be pathogenic (PMID: 15542397, 21031596, 33123925). 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. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at