22-18078607-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_001127649.3(PEX26):c.230+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,445,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: PEX26 NM_001127649.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.69

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-18078607-G-T is Pathogenic according to our data. Variant chr22-18078607-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2159.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.230+1G>T		splice_donor_variant		ENST00000399744.8
PEX26	NM_001199319.2	c.230+1G>T		splice_donor_variant
PEX26	NM_017929.6	c.230+1G>T		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX26	ENST00000399744.8	c.230+1G>T		splice_donor_variant		1	NM_001127649.3	P1
	ENST00000607927.1	n.278C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000830 AC: 12 AN: 1445478 Hom.: 0 Cov.: 30 AF XY: 0.00000418 AC XY: 3 AN XY: 718374

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 17, 2023	- -
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

Nov 20, 2023

This sequence change affects a donor splice site in intron 2 of the PEX26 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Zellweger syndrome (PMID: 16257970, 27392320, 29947050). This variant is also known as intG231T. ClinVar contains an entry for this variant (Variation ID: 2159). 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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 05, 2022

Variant summary: PEX26 c.230+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Furuki_2006). The variant was absent in 213784 control chromosomes. c.230+1G>T has been reported in the literature in individuals affected with Zellweger Syndrome (e.g. Weller_2005, Furuki_2006, Daum_2019). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Weller_2005, Furuki_2006). The most pronounced variant effect results in <10% of normal activity, with the Pex26 variant protein showing only residual protein import function in peroxisomes and immunoblots showing complete absence of protein in human proband fibroblast skin lines (Weller_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.61	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608190; hg19: chr22-18561373;