rs772869377
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000287.4(PEX6):c.2095-21_2095-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
PEX6
NM_000287.4 splice_polypyrimidine_tract, intron
NM_000287.4 splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.291
Genes affected
PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-42966456-TGGAAAGTGCGTG-T is Pathogenic according to our data. Variant chr6-42966456-TGGAAAGTGCGTG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286981.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.2095-21_2095-10del | splice_polypyrimidine_tract_variant, intron_variant | ENST00000304611.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.2095-21_2095-10del | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000287.4 | P1 | |||
PEX6 | ENST00000244546.4 | c.2115+36_2115+47del | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251444Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135906
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461758Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727180
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74274
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2020 | In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15542397) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 11, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 04, 2019 | - - |
Heimler syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change falls in intron 10 of the PEX6 gene. It does not directly change the encoded amino acid sequence of the PEX6 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs772869377, gnomAD 0.02%). This variant has been observed in individuals with Zellweger syndrome (PMID: 15542397, 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 286981). Studies have shown that this variant results in insertion of additional nucleotides and introduces a premature termination codon (PMID: 21520333; external communication). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at