rs62636524

chr1-2412498-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002617.4(PEX10):c.4del(p.Ala2ProfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,364,232 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. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PEX10 NM_002617.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.647

Genes affected

PEX10 (HGNC:8851): (peroxisomal biogenesis factor 10) This gene encodes a protein involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane. Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-2412498-GC-G is Pathogenic according to our data. Variant chr1-2412498-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 449304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX10	NM_002617.4	c.4del	p.Ala2ProfsTer10	frameshift_variant	1/6	ENST00000447513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.4del	p.Ala2ProfsTer10	frameshift_variant	1/6	1	NM_002617.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 34

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 13 AN: 1212216 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 8 AN XY: 592076

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: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PEX10-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2023

The PEX10 c.4delG variant is predicted to result in a frameshift and premature protein termination (p.Ala2Profs*10). This variant along with another truncation variant in this gene was reported in an individual with Zellweger syndrome (Table 4, Steinberg et al 2004. PubMed ID: 15542397). This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-2343937-GC-G). Frameshift variants in PEX10 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Peroxisome biogenesis disorder 6A (Zellweger) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2023

- -

Peroxisome biogenesis disorder 6B Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Mar 23, 2017

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala2Profs*10) in the PEX10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX10 are known to be pathogenic (PMID: 9683594, 10862081, 21031596). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome spectrum (PMID: 15542397). ClinVar contains an entry for this variant (Variation ID: 449304). For these reasons, this variant has been classified as Pathogenic. -

Zellweger spectrum disorders Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2017

The c.4delG variant in the PEX10 gene has been reported previously in an individual with Zellwegersyndrome who also harbored a PEX10 nonsense variant, although parental studies were not performedto determine the phase of these two variants (Steinberg et al., 2004). One functional study indicatedthe c.4delG variant had 23% of PEX transcript in patient skin fibroblasts compared to healthycontrols (Dranchak et al., 2011). The c.4delG variant causes a frameshift starting with codon Alanine2, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 10 ofthe new reading frame, denoted p.A2PfsX10. This variant is predicted to cause loss of normal proteinfunction either through protein truncation or nonsense-mediated mRNA decay. No data are availablefrom control populations to assess the frequency of this variant (Lek et al., 2016). We interpretc.4delG as a pathogenic variant. -

Peroxisome biogenesis disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 29, 2022

Variant summary: PEX10 c.4delG (p.Ala2ProfsX10) 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 1.3e-05 in 150790 control chromosomes (gnomAD v3.1.2). c.4delG has been reported in the literature in at least one compound heterozygous individual affected with Zellweger Syndrome (e.g. Steinberg_2004, Yik_2009). One publication reports experimental evidence indicating that patient fibroblasts with this variant in compound heterozygosity with p.E298X have approximately 23% mutated PEX transcripts compared to healthy controls (Dranchak_2011). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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: rs62636524; hg19: chr1-2343937;