rs61752107

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000286.3(PEX12):c.733_734insGCCT(p.Leu245CysfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

PEX12
NM_000286.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.742

Variant links:

Genes affected

PEX12 (HGNC:8854): (peroxisomal biogenesis factor 12) This gene belongs to the peroxin-12 family. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

PEX12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-35576128-A-AAGGC is Pathogenic according to our data. Variant chr17-35576128-A-AAGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX12	NM_000286.3 linkuse as main transcript	c.733_734insGCCT	p.Leu245CysfsTer19	frameshift_variant	3/3	ENST00000225873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX12	ENST00000225873.9 linkuse as main transcript	c.733_734insGCCT	p.Leu245CysfsTer19	frameshift_variant	3/3	1	NM_000286.3	P1
PEX12	ENST00000586663.2 linkuse as main transcript	c.733_734insGCCT	p.Leu245CysfsTer19	frameshift_variant	3/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249910

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135240

show subpopulations

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:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727224

show subpopulations

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:

0.0000187

Gnomad4 NFE exome

AF:

0.0000971

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000466

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger)

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Leu245Cysfs19) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs61752107, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with peroxisome biogenesis disorders (PMID: 9090384, 19105186). This variant is also known as c.733_734insGCCT. ClinVar contains an entry for this variant (Variation ID: 371737). Studies have shown that this premature translational stop signal alters PEX12 gene expression (PMID: 9090384). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Leu297Thrfs12) have been determined to be pathogenic (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 05, 2017	The PEX12 c.730_733dupGCCT (p.Leu245CysfsTer19) variant has been reported in two studies and identified in three patients in a compound heterozygous state and one patient in a heterozygous state, all with peroxisome biogenesis disorders, with three specifically noted to be in the Zellweger syndrome spectrum (Chang et al. 1997; Steinberg et al. 2004; Yik et al. 2009; Ebberink et al. 2011). All individuals with the variant in a compound heterozygous state had a second insertion variant. Control data are unavailable for the p.Leu245CysfsTer19 variant, but it is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. To evaluate the effect of PEX12 expression on peroxisomal protein import, Chang et al. (1997) used patient fibroblasts and noted that when the variant was present, cDNA expression was observed in the cytoplasm only; however, expression of PEX12 in these cells reversed the effect and import into the peroxisomes was observed. Based on the evidence and due to the potential impact of frameshift variants, the p.Leu245CysfsTer19 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost and replaced with 18 incorrect amino acids. Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9090384, 19105186, 21031596, 19877282, 15542397, 9792857, 29389947) -

Peroxisome biogenesis disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 02, 2018

Variant summary: PEX12 c.730_733dupGCCT (p.Leu245CysfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory, c.888_889delCT (p.Leu297fsX12). The variant allele was found at a frequency of 1.6e-05 in 244662 control chromosomes (gnomAD). The variant, c.730_733dupGCCT has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorders (Chang_1998, Cordoba_2018, Ebberink_2010,Yik_2009). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Chang_1998). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Peroxisome biogenesis disorder type 3B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 16, 2016

- -

PEX12-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This frameshift variant is found in the last exon of PEX12 and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). Truncating variants located downstream of this alteration have been reported in individuals with PEX12-related disorders in the literature (PMID: 26094004). This variant, also referred to as c.733-734insGCCT and c.733-734insGCC (p.L245Cfsx19), has been previously reported as a compound heterozygous change in two individuals with peroxisome biogenesis disorder (PMID: 9090384, 9792857, 15542397, 29389947, 21031596). The c.730_733dup (p.Leu245CysfsTer19) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/249910) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.730_733dup (p.Leu245CysfsTer19) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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