rs61752136

chr22-18083639-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.59

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]

ACMG classification

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
PEX26	NM_001127649.3	c.574C>T	p.Arg192Ter	stop_gained	3/5	ENST00000399744.8
PEX26	NM_017929.6	c.574C>T	p.Arg192Ter	stop_gained	4/6
PEX26	NM_001199319.2	c.574C>T	p.Arg192Ter	stop_gained	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX26	ENST00000399744.8	c.574C>T	p.Arg192Ter	stop_gained	3/5	1	NM_001127649.3	P1
PEX26	ENST00000329627.11	c.574C>T	p.Arg192Ter	stop_gained	4/6	1		P1
PEX26	ENST00000428061.2	c.574C>T	p.Arg192Ter	stop_gained	3/4	1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 33

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

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

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

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

Submissions by phenotype

Peroxisome biogenesis disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 17, 2023	The 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2019	Variant 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2022	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 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 submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -

Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This 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. -

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

Other links and lift over

dbSNP: rs61752136; hg19: chr22-18566405;