rs149806989
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001282678.2(PEX1):c.-78C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,500 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PEX1
NM_001282678.2 5_prime_UTR_premature_start_codon_gain
NM_001282678.2 5_prime_UTR_premature_start_codon_gain
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.25
Genes affected
PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.555
PP5
Variant 7-92517968-G-A is Pathogenic according to our data. Variant chr7-92517968-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517968-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.547C>T | p.Arg183* | stop_gained | 5/24 | ENST00000248633.9 | NP_000457.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.547C>T | p.Arg183* | stop_gained | 5/24 | 1 | NM_000466.3 | ENSP00000248633.4 | ||
PEX1 | ENST00000428214.5 | c.547C>T | p.Arg183* | stop_gained | 5/23 | 1 | ENSP00000394413.1 | |||
PEX1 | ENST00000438045.5 | c.274-4001C>T | intron_variant | 2 | ENSP00000410438.1 | |||||
PEX1 | ENST00000484913.5 | n.586C>T | non_coding_transcript_exon_variant | 5/24 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248528Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134836
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459500Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 725876
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 20, 2023 | - - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 16, 2023 | This sequence change creates a premature translational stop signal (p.Arg183*) 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 (rs149806989, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Zellweger syndrome (PMID: 19105186). ClinVar contains an entry for this variant (Variation ID: 371782). For these reasons, this variant has been classified as Pathogenic. - |
Peroxisome biogenesis disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2018 | Variant summary: PEX1 c.547C>T (p.Arg183X) 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 (eg. c.2097dupT, p.Ile700fsX42; c.2368C>T, p.Arg790X; c.2916delA, p.Gly973fsX16). The variant allele was found at a frequency of 8.2e-06 in 244450 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (8.2e-06 vs 3.90e-03), allowing no conclusion about variant significance. The variant, c.547C>T, has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Yik_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 28, 2021 | - - |
Peroxisome biogenesis disorder 1B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 11, 2016 | - - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 11, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at