NM_000288.4:c.13_19dupTGCGGTG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000288.4(PEX7):c.13_19dupTGCGGTG(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
Consequence
NM_000288.4 frameshift
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX7 | NM_000288.4 | c.13_19dupTGCGGTG | p.Gly7ValfsTer51 | frameshift_variant | Exon 1 of 10 | ENST00000318471.5 | NP_000279.1 | |
PEX7 | XM_006715502.3 | c.13_19dupTGCGGTG | p.Gly7ValfsTer51 | frameshift_variant | Exon 1 of 7 | XP_006715565.1 | ||
PEX7 | XM_047418874.1 | c.13_19dupTGCGGTG | p.Gly7ValfsTer51 | frameshift_variant | Exon 1 of 6 | XP_047274830.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX7 | ENST00000318471.5 | c.13_19dupTGCGGTG | p.Gly7ValfsTer51 | frameshift_variant | Exon 1 of 10 | 1 | NM_000288.4 | ENSP00000315680.3 | ||
PEX7 | ENST00000367756.8 | c.13_19dupTGCGGTG | p.Gly7ValfsTer51 | frameshift_variant | Exon 1 of 4 | 3 | ENSP00000356730.4 | |||
PEX7 | ENST00000541292.6 | n.13_19dupTGCGGTG | non_coding_transcript_exon_variant | Exon 1 of 11 | 5 | ENSP00000441004.1 | ||||
PEX7 | ENST00000678593.1 | n.13_19dupTGCGGTG | non_coding_transcript_exon_variant | Exon 1 of 8 | ENSP00000503841.1 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151476Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.00000806 AC: 1AN: 124026Hom.: 0 AF XY: 0.0000147 AC XY: 1AN XY: 68092
GnomAD4 exome AF: 0.00000364 AC: 5AN: 1373330Hom.: 0 Cov.: 33 AF XY: 0.00000443 AC XY: 3AN XY: 677906
GnomAD4 genome AF: 0.0000264 AC: 4AN: 151476Hom.: 0 Cov.: 35 AF XY: 0.0000406 AC XY: 3AN XY: 73962
ClinVar
Submissions by phenotype
Rhizomelic chondrodysplasia punctata type 1 Pathogenic:3Other:1
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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
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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). For these reasons, this variant has been classified as Pathogenic. -
Rhizomelic chondrodysplasia punctata Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at