rs762679408
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000466.3(PEX1):c.5G>A(p.Trp2Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,838 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: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
PEX1
NM_000466.3 stop_gained
NM_000466.3 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.55
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 282 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-92528431-C-T is Pathogenic according to our data. Variant chr7-92528431-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92528431-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.5G>A | p.Trp2Ter | stop_gained | 1/24 | ENST00000248633.9 | |
PEX1 | NM_001282677.2 | c.5G>A | p.Trp2Ter | stop_gained | 1/23 | ||
PEX1 | XM_047420472.1 | c.5G>A | p.Trp2Ter | stop_gained | 1/23 | ||
PEX1 | NM_001282678.2 | c.-655G>A | 5_prime_UTR_variant | 1/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.5G>A | p.Trp2Ter | stop_gained | 1/24 | 1 | NM_000466.3 | P1 | |
PEX1 | ENST00000428214.5 | c.5G>A | p.Trp2Ter | stop_gained | 1/23 | 1 | |||
PEX1 | ENST00000438045.5 | c.5G>A | p.Trp2Ter | stop_gained | 1/21 | 2 | |||
PEX1 | ENST00000484913.5 | n.9G>A | non_coding_transcript_exon_variant | 1/24 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000148 AC: 3AN: 202846Hom.: 0 AF XY: 0.00000900 AC XY: 1AN XY: 111086
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GnomAD4 exome AF: 0.00000348 AC: 5AN: 1437838Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1AN XY: 713146
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Zellweger spectrum disorders Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2023 | This sequence change creates a premature translational stop signal (p.Trp2*) 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 (rs762679408, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with a PEX1-related condition (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 558040). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 30, 2017 | - - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 02, 2023 | - - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 02, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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