rs1057516641
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000288.4(PEX7):c.13_19dup(p.Gly7ValfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000059 in 1,524,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0000036 ( 0 hom. )
Consequence
PEX7
NM_000288.4 frameshift
NM_000288.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.09
Genes affected
PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]
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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 97 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 6-136822669-A-AGTGCGGT is Pathogenic according to our data. Variant chr6-136822669-A-AGTGCGGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX7 | NM_000288.4 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant | 1/10 | ENST00000318471.5 | |
PEX7 | XM_006715502.3 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant | 1/7 | ||
PEX7 | XM_047418874.1 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX7 | ENST00000318471.5 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant | 1/10 | 1 | NM_000288.4 | P1 | |
PEX7 | ENST00000367756.8 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant | 1/4 | 3 | |||
PEX7 | ENST00000541292.6 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant, NMD_transcript_variant | 1/11 | 5 | |||
PEX7 | ENST00000678593.1 | c.13_19dup | p.Gly7ValfsTer51 | frameshift_variant, NMD_transcript_variant | 1/8 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151476Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.00000806 AC: 1AN: 124026Hom.: 0 AF XY: 0.0000147 AC XY: 1AN XY: 68092
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GnomAD4 exome AF: 0.00000364 AC: 5AN: 1373330Hom.: 0 Cov.: 33 AF XY: 0.00000443 AC XY: 3AN XY: 677906
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rhizomelic chondrodysplasia punctata type 1 Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 13, 2021 | Variant summary: PEX7 c.13_19dupTGCGGTG (p.Gly7ValfsX51) 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 8.1e-06 in 124026 control chromosomes. c.13_19dupTGCGGTG has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Refsum disease (Rhizomelic Chondrodysplasia Punctata Type 1) and has been subsequently cited by others (example, van den Brink_2003, Jansen_2004, Nanetti_2015). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although the reported compound heterozygous patient had defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. 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 9B Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change creates a premature translational stop signal (p.Gly7Valfs*51) in the PEX7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX7 are known to be pathogenic (PMID: 12325024, 12522768, 20301447). This variant is present in population databases (rs62636519, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Refsum disease (PMID: 12522768). ClinVar contains an entry for this variant (Variation ID: 370629). For these reasons, this variant has been classified as Pathogenic. - |
Rhizomelic chondrodysplasia punctata Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 02, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at