chr17-35577895-C-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000286.3(PEX12):c.126+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000144 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000286.3 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX12 | ENST00000225873.9 | c.126+1G>T | splice_donor_variant, intron_variant | Intron 1 of 2 | 1 | NM_000286.3 | ENSP00000225873.3 | |||
PEX12 | ENST00000586663.2 | n.126+1G>T | splice_donor_variant, intron_variant | Intron 1 of 2 | 1 | ENSP00000466894.2 | ||||
PEX12 | ENST00000585380.1 | c.126+1G>T | splice_donor_variant, intron_variant | Intron 2 of 2 | 4 | ENSP00000466280.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251312Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135862
GnomAD4 exome AF: 0.000153 AC: 223AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.000155 AC XY: 113AN XY: 727222
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:4
- -
- -
- -
Observed with a second PEX12 variant on the opposite allele (in trans) in individuals with Zellweger spectrum disorders in published literature (Chang and Gould, 1998; Demaret et al., 2018).; Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15542397, 9632816, 9090384, 16199547, 33123925, 21031596, 29453832, 22871920, 31980526, 9792857) -
Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:3
- -
This sequence change affects a donor splice site in intron 1 of the PEX12 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). This variant is present in population databases (rs144259891, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with PEX12-related conditions (PMID: 9792857, 21031596). ClinVar contains an entry for this variant (Variation ID: 371718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
NM_000286.2(PEX12):c.126+1G>T is a canonical splice variant classified as pathogenic in the context of peroxisome biogenesis disorder type 3. c.126+1G>T has been observed in cases with relevant disease (PMID: 9792857, 21031596). Functional assessments of this variant are available in the literature (PMID: 9792857). c.126+1G>T has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000286.2(PEX12):c.126+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Peroxisome biogenesis disorder Pathogenic:1
Variant summary: The PEX12 c.126+1G>T variant involves the alteration of a conserved intronic nucleotide 1 base pair upstream of the exon-intron junction. Mutation Taster predicts a damaging outcome for this variant and 5/5 splice prediction tools predict a significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExACat a frequency of 0.0000329 (4/121406 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX12 variant (0.0015811). Multiple publications have detected and analyzed the variant in patient cohorts. Chang_AJHG_1998 detected the variant in two patients (PBD006 [severely affected] and PBD099 [mildly affected]), both of which were compound heterozygotes, each carrying a different second mutation allele (PBD006 - p.R180ter; PBD099 - c.26_27delCA causing a frameshift). Functional analyses showed a significant reduction in PBD006 mRNA levels (14% of WT levels) and a lesser reduction in PBD099 (70% of WT levels). Additional molecular studies showed that the c.26_27delCA mutation is a partially functional allele, accounting for the differences observed in phenotype severity and mRNA levels, and supporting a pathogenic role for the variant of interest. Another publication, Ebberink_HM_2011, performed high-throughput complementation assays in 613 patient skin fibroblast cell lines and detected the variant of interest in 8 patients (3 homozygous and 5 heterozygous). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at