rs267608239
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000287.4(PEX6):c.2356C>T(p.Arg786Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,890 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R786Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000287.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.2356C>T | p.Arg786Trp | missense_variant | 12/17 | ENST00000304611.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.2356C>T | p.Arg786Trp | missense_variant | 12/17 | 1 | NM_000287.4 | P1 | |
PEX6 | ENST00000244546.4 | c.2116-261C>T | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461734Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727172
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Cerebellar ataxia;C0018784:Sensorineural hearing loss disorder;C0025322:Premature ovarian insufficiency;C0031117:Peripheral neuropathy;C0338656:Cognitive impairment;C0393588:Paroxysmal dystonia Pathogenic:1
Pathogenic, no assertion criteria provided | research | Reproductive Development, Murdoch Childrens Research Institute | Oct 21, 2019 | - - |
Heimler syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 08, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 29, 2017 | - - |
Peroxisome biogenesis disorder 4A (Zellweger) Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Sep 26, 2019 | - - |
Peroxisome biogenesis disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 786 of the PEX6 protein (p.Arg786Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Zellweger Syndrome Spectrum (PMID: 25079577, 32399598). ClinVar contains an entry for this variant (Variation ID: 553552). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at