rs74315506
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong
The NM_001127649.3(PEX26):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,764 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001127649.3 start_lost
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX26 | NM_001127649.3 | c.2T>C | p.Met1? | start_lost | Exon 1 of 5 | ENST00000399744.8 | NP_001121121.1 | |
PEX26 | NM_017929.6 | c.2T>C | p.Met1? | start_lost | Exon 2 of 6 | NP_060399.1 | ||
PEX26 | NM_001199319.2 | c.2T>C | p.Met1? | start_lost | Exon 2 of 5 | NP_001186248.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX26 | ENST00000399744.8 | c.2T>C | p.Met1? | start_lost | Exon 1 of 5 | 1 | NM_001127649.3 | ENSP00000382648.4 | ||
ENSG00000288683 | ENST00000474897.6 | n.2T>C | non_coding_transcript_exon_variant | Exon 2 of 9 | 5 | ENSP00000434235.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1447764Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 719838
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:2
- -
This sequence change affects the initiator methionine of the PEX26 mRNA. The next in-frame methionine is located at codon 96. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with PEX26-related conditions (PMID: 12851857). ClinVar contains an entry for this variant (Variation ID: 2156). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PEX26 function (PMID: 12851857). This variant disrupts a region of the PEX26 protein in which other variant(s) (p.Gly89Arg) have been determined to be pathogenic (PMID: 12851857). 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. -
Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1
The PEX26 c.2T>C (p.Met1?) variant is predicted to disrupt the initiator codon and thus may interfere with protein expression. This variant has been reported in two individuals with infantile Refsum disease, both of whom were compound heterozygous for this variant and the same missense variant (Matsumoto et al. 2003; Weller et al. 2005). Another variant (c.3T>C) that results in the same protein consequence has been reported in a compound heterozygous state in an individual with hearing loss and enamel defects, consistent with Heimler syndrome (Neuhaus et al. 2017). The p.Met1? variant was absent from 106 control chromosomes but is reported at a frequency of 0.000062 in the East Asian population of the Genome Aggregation Database. However, this frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Studies in patient and non-patient cells have demonstrated that the variant impairs protein function, including less effective recruitment of Pex1p-Pex6p complexes to peroxisomes and reduced peroxisomal protein import (Matsumoto et al. 2003; Weller et al. 2005; Furuki et al. 2006). Due to the potential impact of initiator codon variants and the available literature, the p.Met1? variant is classified as likely pathogenic for Zellweger syndrome spectrum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided Pathogenic:1
Initiation codon variant 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: 25525159, 12851857, 15858711, 16257970) -
Peroxisome biogenesis disorder 7B Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at