rs1258472160
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000287.4(PEX6):βc.1287delβ(p.Trp430GlyfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L429L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000287.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.1287del | p.Trp430GlyfsTer20 | frameshift_variant | 5/17 | ENST00000304611.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.1287del | p.Trp430GlyfsTer20 | frameshift_variant | 5/17 | 1 | NM_000287.4 | P1 | |
PEX6 | ENST00000244546.4 | c.1287del | p.Trp430GlyfsTer20 | frameshift_variant | 5/15 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461606Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727110
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
PEX6-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 13, 2023 | The PEX6 c.1287delC variant is predicted to result in a frameshift and premature protein termination (p.Trp430Glyfs*20). This variant was reported in the compound heterozygous state in two siblings with peroxisomal disorders (Gagnon et al. 2023. PubMed ID: 36649687). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in PEX6 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Zellweger spectrum disorders Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Heimler syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 08, 2023 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change creates a premature translational stop signal (p.Trp430Glyfs*20) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PEX6-related conditions. ClinVar contains an entry for this variant (Variation ID: 446026). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 27, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at