rs61750428
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000466.3(PEX1):c.2992C>T(p.Arg998Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000155 in 1,613,700 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R998R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000466.3 stop_gained
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.2992C>T | p.Arg998Ter | stop_gained | 19/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.2992C>T | p.Arg998Ter | stop_gained | 19/24 | 1 | NM_000466.3 | P1 | |
ENST00000658444.1 | n.3663G>A | non_coding_transcript_exon_variant | 2/2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152108Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250908Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135598
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461592Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727106
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152108Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74294
ClinVar
Submissions by phenotype
Heimler syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 07, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 11, 2015 | - - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This sequence change creates a premature translational stop signal (p.Arg998*) 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). This variant is present in population databases (rs61750428, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with PEX1-related conditions (PMID: 12402331, 19105186). ClinVar contains an entry for this variant (Variation ID: 495880). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2023 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2023 | Variant summary: PEX1 c.2992C>T (p.Arg998X) 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 allele was found at a frequency of 8e-06 in 250908 control chromosomes. c.2992C>T has been reported in the literature in individuals affected with Zellweger Syndrome (Yik_2009, Maxwell_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Peroxisome biogenesis disorder 1B Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 11, 2015 | - - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 11, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at