rs61752108

Variant names:

• chr17-35576117-T-TA
• rs61752108
• NM_000286.3:c.744dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000286.3(PEX12):​c.744dupT​(p.Thr249TyrfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S248S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PEX12 NM_000286.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.989
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35576117-T-TA is Pathogenic according to our data. Variant chr17-35576117-T-TA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 553741.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	c.744dupT	p.Thr249TyrfsTer14	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	c.744dupT	p.Thr249TyrfsTer14	frameshift_variant	Exon 3 of 3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000586663.2	n.744dupT		non_coding_transcript_exon_variant	Exon 3 of 3	1		ENSP00000466894.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250122 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41418

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:3

Apr 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 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.Thr249Tyrfs*14) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 111 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs61752108, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 9090384, 9792857). This variant is also known as c.744_745insT. ClinVar contains an entry for this variant (Variation ID: 553741). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PEX12 function (PMID: 9090384). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Leu297Thrfs*12) 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. -

Sep 25, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 21, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a variant on the opposite allele (in trans) in a patient with Zellweger syndrome in the published literature (Chang et al., 1997; Chang and Gould, 1998; Ebberink et al., 2011); Frameshift variant predicted to result in protein truncation, as the last 111 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9090384, 9792857, 21031596) -

Peroxisome biogenesis disorder Pathogenic:1

Jun 06, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PEX12 c.744dupT (p.Thr249TyrfsX14) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250122 control chromosomes (gnomAD). c.744dupT has been reported in the literature in individuals affected with Zellweger Syndrome (e.g. Chang_1997, Ebberink_2011). One of these patients was shown to have impaired PTS1- and PTS2-protein transport, and reduced PEX12 mRNA levels (Chang_1998). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Sep 08, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: -33

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

Other links and lift over

dbSNP: rs61752108; hg19: chr17-33903136;