6-42965712-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000287.4(PEX6):c.2440C>T(p.Arg814Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000684 in 1,461,588 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
PEX6
NM_000287.4 stop_gained
NM_000287.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.85
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-42965712-G-A is Pathogenic according to our data. Variant chr6-42965712-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 194165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42965712-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.2440C>T | p.Arg814Ter | stop_gained | 13/17 | ENST00000304611.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.2440C>T | p.Arg814Ter | stop_gained | 13/17 | 1 | NM_000287.4 | P1 | |
PEX6 | ENST00000244546.4 | c.2193C>T | p.Gly731= | synonymous_variant | 11/15 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251478Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461588Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727108
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 13, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2019 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19877282, 25525159, 31589614, 33213396, 31884617) - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Heimler syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 24, 2020 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Arg814*) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is present in population databases (rs267608241, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Zellweger Syndrome Spectrum (PMID: 19877282). ClinVar contains an entry for this variant (Variation ID: 194165). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Peroxisome biogenesis disorder 4B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 14, 2017 | - - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;D
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