rs62642859
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000286.3(PEX12):c.684_687del(p.Ser229ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V228V) has been classified as Likely benign.
Frequency
Consequence
NM_000286.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX12 | NM_000286.3 | c.684_687del | p.Ser229ArgfsTer3 | frameshift_variant | 3/3 | ENST00000225873.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX12 | ENST00000225873.9 | c.684_687del | p.Ser229ArgfsTer3 | frameshift_variant | 3/3 | 1 | NM_000286.3 | P1 | |
PEX12 | ENST00000586663.2 | c.684_687del | p.Ser229ArgfsTer3 | frameshift_variant | 3/3 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248992Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134794
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461774Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727164
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Ser229Argfs*3) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 131 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs62642859, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of peroxisomal biogenesis disorders (PMID: 9090384). ClinVar contains an entry for this variant (Variation ID: 371738). 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1997 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 16, 2016 | - - |
Peroxisome biogenesis disorder type 3B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 16, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at