chr22-18083639-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001127649.3(PEX26):​c.574C>T​(p.Arg192Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,874 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: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PEX26
NM_001127649.3 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.59
Variant links:
Genes affected
PEX26 (HGNC:22965): (peroxisomal biogenesis factor 26) This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]

Genome browser will be placed here

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 22-18083639-C-T is Pathogenic according to our data. Variant chr22-18083639-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 928563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18083639-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PEX26NM_001127649.3 linkuse as main transcriptc.574C>T p.Arg192Ter stop_gained 3/5 ENST00000399744.8
PEX26NM_017929.6 linkuse as main transcriptc.574C>T p.Arg192Ter stop_gained 4/6
PEX26NM_001199319.2 linkuse as main transcriptc.574C>T p.Arg192Ter stop_gained 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PEX26ENST00000399744.8 linkuse as main transcriptc.574C>T p.Arg192Ter stop_gained 3/51 NM_001127649.3 P1Q7Z412-1
PEX26ENST00000329627.11 linkuse as main transcriptc.574C>T p.Arg192Ter stop_gained 4/61 P1Q7Z412-1
PEX26ENST00000428061.2 linkuse as main transcriptc.574C>T p.Arg192Ter stop_gained 3/41 Q7Z412-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152074
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251294
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461800
Hom.:
0
Cov.:
32
AF XY:
0.0000165
AC XY:
12
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152074
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000473
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 06, 2019Variant summary: PEX26 c.574C>T (p.Arg192X) 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. The variant allele was found at a frequency of 2e-05 in 251294 control chromosomes (gnomAD). c.574C>T has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Steinberg_2004). These data indicate that the variant may be associated with disease. A publication, Guder_2019, performed a functional study to assess the pathophysiological relevance of PEX26 oligomerization and found the variant of interest to not oligomerize but was still able to interact with PEX6. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 17, 2023The PEX26 c.574C>T (p.Arg192Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported with a second pathogenic PEX26 variant in an individual with clinical and laboratory features consistent with peroxisome biogenesis disorder (PMID: 15542397). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database and has been classified as pathogenic by at least three submitters in ClinVar. The c.574C>T variant was detected in a homozygous state. Based on the available evidence, the c.574C>T (p.Arg192Ter) variant is classified as pathogenic for peroxisome biogenesis disorder. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 14, 2022Nonsense 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34804114, 25525159, 34426522, 12851857, 15542397, 19105186, 21031596) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 26, 2023- -
Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 19, 2023This sequence change creates a premature translational stop signal (p.Arg192*) in the PEX26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). 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 premature translational stop signal has been observed in individual(s) with peroxisome biogenesis disorders-Zellweger syndrome spectrum (PMID: 15542397). ClinVar contains an entry for this variant (Variation ID: 928563). For these reasons, this variant has been classified as Pathogenic. -
Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 07, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Uncertain
0.42
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.94
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.18
GERP RS
4.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61752136; hg19: chr22-18566405; API