22-18078379-G-A

Variant names:

• chr22-18078379-G-A
• NM_001127649.3:c.3G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001127649.3(PEX26):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX26 NM_001127649.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.42

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]

ENSG00000288683 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 96 codons. Genomic position: 18079929. Lost 0.312 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-18078379-G-A is Pathogenic according to our data. Variant chr22-18078379-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3759598.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-18078379-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.3G>A	p.Met1?	start_lost	Exon 2 of 6		NP_060399.1
PEX26	NM_001199319.2	c.3G>A	p.Met1?	start_lost	Exon 2 of 5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.3G>A		non_coding_transcript_exon_variant	Exon 2 of 9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PEX26 mRNA. The next in-frame methionine is located at codon 96. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with PEX26-related conditions (PMID: 12851857, 28944237). This variant disrupts a region of the PEX26 protein in which other variant(s) (p.Gly89Arg ) have been determined to be pathogenic (PMID: 12851857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	.;T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;.;D;.
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
PROVEAN	Benign	-1.9	.;N;N;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.90
MutPred		0.71		Gain of methylation at K2 (P = 0.0387);Gain of methylation at K2 (P = 0.0387);Gain of methylation at K2 (P = 0.0387);Gain of methylation at K2 (P = 0.0387);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.91
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 26

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-18561145;