rs61752133

Positions:

• chr22-18079896-C-CT

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.254dup​(p.Cys86ValfsTer29) variant causes a frameshift change. The variant allele was found at a frequency of 0.000013 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L85L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PEX26 NM_001127649.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.43

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 22-18079896-C-CT is Pathogenic according to our data. Variant chr22-18079896-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 2158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX26	NM_001127649.3	c.254dup	p.Cys86ValfsTer29	frameshift_variant	2/5	ENST00000399744.8
PEX26	NM_001199319.2	c.254dup	p.Cys86ValfsTer29	frameshift_variant	3/5
PEX26	NM_017929.6	c.254dup	p.Cys86ValfsTer29	frameshift_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX26	ENST00000399744.8	c.254dup	p.Cys86ValfsTer29	frameshift_variant	2/5	1	NM_001127649.3	P1
PEX26	ENST00000329627.11	c.254dup	p.Cys86ValfsTer29	frameshift_variant	3/6	1		P1
PEX26	ENST00000428061.2	c.254dup	p.Cys86ValfsTer29	frameshift_variant	2/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000349 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

This sequence change creates a premature translational stop signal (p.Cys86Valfs*29) 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). This variant is present in population databases (rs779824948, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum disorder (PMID: 12851857). ClinVar contains an entry for this variant (Variation ID: 2158). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PEX26 function (PMID: 12851857, 16257970). For these reasons, this variant has been classified as Pathogenic. -

Peroxisome biogenesis disorder 7B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

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: rs61752133; hg19: chr22-18562662;