rs398123301

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000286.3(PEX12):c.888_889delCT(p.Leu297ThrfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L296L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PEX12
NM_000286.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: -0.0120

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 3A (Zellweger)
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
peroxisome biogenesis disorder type 3B
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 19 pathogenic variants in the truncated region.

PP5

Variant 17-35575972-AAG-A is Pathogenic according to our data. Variant chr17-35575972-AAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX12	NM_000286.3 link	c.888_889delCT	p.Leu297ThrfsTer12	frameshift_variant	Exon 3 of 3	ENST00000225873.9	NP_000277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX12	ENST00000225873.9 link	c.888_889delCT	p.Leu297ThrfsTer12	frameshift_variant	Exon 3 of 3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000586663.2 link	n.888_889delCT		non_coding_transcript_exon_variant	Exon 3 of 3	1		ENSP00000466894.2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000127

AC:

AN:

251446

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461876

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1111996

Other (OTH)

AF:

0.000149

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000243

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41550

American (AMR)

AF:

0.00111

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000234

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger)

Pathogenic:4

Jan 06, 2020

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, 14571262, 15542397 and 21031596. Classification of NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -

Nov 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 20, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu297Thrfs*12) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs398123301, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with PEX12-related conditions (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). ClinVar contains an entry for this variant (Variation ID: 92776). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:4

Jan 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation, as the last 63 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Also known as c.887_888delTC using alternate nomenclature; This variant is associated with the following publications: (PMID: 31395954, 9792857, 34426522, 31589614, 21031596, 32005694, 34440436, 15542397, 29619570, 14571262, 32483926, 26094004) -

Peroxisome biogenesis disorder type 3B

Pathogenic:2

Jan 06, 2020

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1,PM3 (strong),PM2 -

Inborn genetic diseases

Pathogenic:1

Sep 22, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.888_889delCT (p.L297Tfs*12) alteration, located in exon 3 (coding exon 3) of the PEX12 gene, consists of a deletion of 2 nucleotides from position 888 to 889, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration occurs at the 3' terminus of the PEX12 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 17% of the protein. Premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in multiple individuals with PEX12-related peroxisome biogenesis disorder, in the homozygous state, the compound heterozygous state, and in the heterozygous state without a second alteration identified (Chang, 1998; Ebberink, 2011; Gootjes, 2004; Konkoová, 2015; Salpietro, 2015; Steinberg, 2004; Wojcik, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Peroxisome biogenesis disorder

Pathogenic:1

Jul 21, 2016

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PEX12 c.888_889delCT (p.Leu297Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX12 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121406 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX12 variant (0.0015811). The variant has been identified in multiple affected individuals in heterozygous and homozygous state. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger)

Pathogenic:1

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PEX12-related disorder

Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PEX12 c.888_889delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu297Thrfs*12). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Zellweger syndrome (Chang and Gould 1998. PubMed ID: 9792857; Gootjes et al. 2004. PubMed ID: 14571262; Ebberink et al. 2011. PubMed ID: 21031596; Salpietro et al. 2015. PubMed ID: 25287621). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. Frameshift variants in PEX12 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.012

Mutation Taster

=13/187

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over