rs398123301

chr17-35575972-AAG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000286.3(PEX12):c.888_889del(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: -0.0120

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]

ACMG classification

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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35575972-AAG-A is Pathogenic according to our data. Variant chr17-35575972-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 92776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35575972-AAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX12	NM_000286.3	c.888_889del	p.Leu297ThrfsTer12	frameshift_variant	3/3	ENST00000225873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX12	ENST00000225873.9	c.888_889del	p.Leu297ThrfsTer12	frameshift_variant	3/3	1	NM_000286.3	P1
PEX12	ENST00000586663.2	c.888_889del	p.Leu297ThrfsTer12	frameshift_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152162 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251446 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135892

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 SAS exome AF: 0.0000327

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.: 0 AF XY: 0.000103 AC XY: 75 AN XY: 727234

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74468

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000234

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2023	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2023	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, 26094004, 14571262, 32483926) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 21, 2016

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 06, 2020

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. -

Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs398123301; hg19: chr17-33902991;