rs61752136

Variant names:

• chr22-18083639-C-T
• rs61752136
• NM_001127649.3:c.574C>T
• PEX26 p.Arg192*

Your query was ambiguous. Multiple possible variants found:

• chr22-18083639-C-T
• chr22-18083639-C-A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001127649.3(PEX26):​c.574C>T​(p.Arg192*) 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 (★★). ClinVar reports functional evidence for this variant: "SCV001360943: 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.". 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.59
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P
• 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001360943: 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.
• 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 VariationId is 928563.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.574C>T	p.Arg192*	stop_gained	Exon 3 of 5	NP_001121121.1	Q7Z412-1
	PEX26	NM_017929.6		c.574C>T	p.Arg192*	stop_gained	Exon 4 of 6	NP_060399.1	Q7Z412-1
	PEX26	NM_001199319.2		c.574C>T	p.Arg192*	stop_gained	Exon 4 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.574C>T	p.Arg192*	stop_gained	Exon 3 of 5	ENSP00000382648.4	Q7Z412-1
	PEX26	ENST00000329627.11	TSL:1	c.574C>T	p.Arg192*	stop_gained	Exon 4 of 6	ENSP00000331106.5	Q7Z412-1
	PEX26	ENST00000428061.2	TSL:1	c.574C>T	p.Arg192*	stop_gained	Exon 3 of 4	ENSP00000412441.2	Q7Z412-2

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251294 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74284

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0763859), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000360 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Peroxisome biogenesis disorder 7A (Zellweger) (3)
2	-	-	not provided (2)
2	-	-	Peroxisome biogenesis disorder (2)
2	-	-	Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.6
Mutation Taster		=2/198	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61752136;

hg19: chr22-18566405;