chr22-18078379-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

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, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.42
• Publications: 0 publications found

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]

PEX26 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 7A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 7B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288683 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 22 pathogenic variants. Next in-frame start position is after 96 codons. Genomic position: 18079929. Lost 0.312 part of the original CDS.
• PS1: Another start lost variant in NM_001127649.3 (PEX26) was described as [Likely_pathogenic] in ClinVar
• 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 VariationId is 3759598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127649.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	NM_001127649.3	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	NP_001121121.1	Q7Z412-1
	PEX26	NM_017929.6		c.3G>A	p.Met1?	start_lost	Exon 2 of 6	NP_060399.1	Q7Z412-1
	PEX26	NM_001199319.2		c.3G>A	p.Met1?	start_lost	Exon 2 of 5	NP_001186248.1	Q7Z412-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	ENST00000399744.8	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	ENSP00000382648.4	Q7Z412-1
	PEX26	ENST00000329627.11	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 6	ENSP00000331106.5	Q7Z412-1
	PEX26	ENST00000428061.2	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 4	ENSP00000412441.2	Q7Z412-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.4
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.71		Gain of methylation at K2 (P = 0.0387)
MVP		0.98
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		0.018	Neutral
Varity_R		0.91
gMVP		0.55
Mutation Taster		=5/195	disease causing

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

Other links and lift over

hg19: chr22-18561145;