rs786204606
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000466.3(PEX1):βc.1716_1717delβ(p.His572GlnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,744 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. H572H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000466.3 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 |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.1716_1717del | p.His572GlnfsTer19 | frameshift_variant | 10/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.1716_1717del | p.His572GlnfsTer19 | frameshift_variant | 10/24 | 1 | NM_000466.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461642Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727144
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74278
ClinVar
Submissions by phenotype
Zellweger spectrum disorders Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188984). This premature translational stop signal has been observed in individuals with peroxisomal biogenesis disorders (PMID: 19105186). This variant is present in population databases (rs786204606, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.His572Glnfs*19) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 30, 2017 | - - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2020 | Variant summary: PEX1 c.1716_1717delCA (p.His572GlnfsX19) 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 was absent in 251424 control chromosomes (gnomAD). c.1716_1717delCA has been reported in the literature in individuals affected with Zellweger Syndrome (examples- Yik_2009, Ebberink_2010). 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 prior to or in 2014) cited the variant as pathogenic/likley pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 25, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at