rs776731688

Variant names:

• chr17-35577384-G-A
• rs776731688
• NM_000286.3:c.334C>T

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.334C>T​(p.Gln112*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,782 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX12 NM_000286.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.92
• 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35577384-G-A is Pathogenic according to our data. Variant chr17-35577384-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 191074.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.334C>T	p.Gln112*	stop_gained	Exon 2 of 3	ENST00000225873.9	NP_000277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX12	ENST00000225873.9	c.334C>T	p.Gln112*	stop_gained	Exon 2 of 3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000586663.2	n.334C>T		non_coding_transcript_exon_variant	Exon 2 of 3	1		ENSP00000466894.2
PEX12	ENST00000585380.1	c.334C>T	p.Gln112*	stop_gained	Exon 3 of 3	4		ENSP00000466280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251234 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 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: 53392

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:4

Jan 31, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 2 of 3 encodes for a premature stop codon and is predicted to result in loss of normal protein function. This variant has been previously reported as a homozygous change in association with intellectual disability and inborn error of metabolism (PMID: 27124789). It is absent from the gnomAD population database and is present in the heterozygous state in the ExAC population database at a frequency of 0.001% (1/120740) and thus is presumed to be rare. This variant has been classified in ClinVar as a pathogenic and likely pathogenic variant (Variation ID: 191074). In silico analyses support a deleterious effect of the c.334C>T (p.Gln112Ter) variant on protein function. Based on the available evidence, the c.334C>T (p.Gln112Ter) variant is classified as pathogenic. -

Oct 26, 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.Gln112*) in the PEX12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). This variant is present in population databases (rs776731688, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PEX12-related conditions. ClinVar contains an entry for this variant (Variation ID: 191074). For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Dec 11, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21031596, 25326635, 27124789, 33123925) -

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Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

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

Jun 07, 2018

Counsyl

Significance: Likely 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. -

PEX12-related disorder Pathogenic:1

Jul 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PEX12 c.334C>T variant is predicted to result in premature protein termination (p.Gln112*). This variant was reported in fetus with neurological and other congenital anomalies (Yang et al 2014. PubMed ID: 25326635). To our knowledge, it has not been reported in individuals with peroxisomal storage disorder. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-33904403-G-A). Nonsense variants in PEX12 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		3.9
Vest4		0.84
GERP RS		5.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs776731688; hg19: chr17-33904403;