rs61750409
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000248633.9(PEX1):c.1897C>T(p.Arg633Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000642 in 1,557,706 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. R633R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000248633.9 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.1897C>T | p.Arg633Ter | stop_gained | 11/24 | ENST00000248633.9 | NP_000457.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.1897C>T | p.Arg633Ter | stop_gained | 11/24 | 1 | NM_000466.3 | ENSP00000248633 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151864Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251234Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135806
GnomAD4 exome AF: 0.00000640 AC: 9AN: 1405842Hom.: 0 Cov.: 25 AF XY: 0.00000853 AC XY: 6AN XY: 703070
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151864Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74140
ClinVar
Submissions by phenotype
PEX1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2023 | The PEX1 c.1897C>T variant is predicted to result in premature protein termination (p.Arg633*). This variant has been reported in patients with PEX1-related disorders (Patient E-13 in Tamura et al. 2001. PubMed ID: 11439091; Abualsaud et al. 2020. PubMed ID: 32949114; Shamseldin et al. 2021. PubMed ID: 34645488; Rosewich et al. 2005. PubMed ID: 16141001). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92135565-G-A). Nonsense variants in PEX1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 29, 2023 | - - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 550841). This premature translational stop signal has been observed in individual(s) with PEX1-related conditions (PMID: 11439091). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg633*) 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: 9398847, 16086329, 16141001, 21031596, 26387595, 31831025). - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2022 | Variant summary: PEX1 c.1897C>T (p.Arg633X) 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 4e-06 in 251234 control chromosomes. c.1897C>T has been reported in the literature in individuals affected with Peroxisome Biogenesis Disorder/Zellweger syndrome (example, Piscosquito_2016, Rosewich_2005, Tamura_2001, Alshenaifi_2019). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 24, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at