rs61752103
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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.538C>T(p.Arg180Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )
Consequence
PEX12
NM_000286.3 stop_gained
NM_000286.3 stop_gained
Scores
2
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2
Clinical Significance
Conservation
PhyloP100: 2.45
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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.502 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-35577180-G-A is Pathogenic according to our data. Variant chr17-35577180-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX12 | NM_000286.3 | c.538C>T | p.Arg180Ter | stop_gained | 2/3 | ENST00000225873.9 | NP_000277.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX12 | ENST00000225873.9 | c.538C>T | p.Arg180Ter | stop_gained | 2/3 | 1 | NM_000286.3 | ENSP00000225873 | P1 | |
PEX12 | ENST00000586663.2 | c.538C>T | p.Arg180Ter | stop_gained | 2/3 | 1 | ENSP00000466894 | |||
PEX12 | ENST00000585380.1 | c.538C>T | p.Arg180Ter | stop_gained | 3/3 | 4 | ENSP00000466280 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152060Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251490Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135916
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GnomAD4 exome AF: 0.0000410 AC: 60AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727242
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 152060Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74264
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Arg180*) in the PEX12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). This variant is present in population databases (rs61752103, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of Zellweger syndrome (PMID: 9792857, 24627108). ClinVar contains an entry for this variant (Variation ID: 7774). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2017 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2019 | Variant summary: PEX12 c.538C>T (p.Arg180X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 251490 control chromosomes (gnomAD). c.538C>T has been reported in the literature in individuals affected with Zellweger Syndrome (Okumoto_1998, Chang_1998, Schabhuttl_2014, Gootjes_2004, Dranchak_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisomal biogenesis disorder 3b Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2004 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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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