rs61752093

Positions:

• chr1-2406580-CAG-C

Variant summary

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

The NM_002617.4(PEX10):​c.814_815del​(p.Leu272ValfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,414 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. L272L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: PEX10 NM_002617.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 0.566

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-2406580-CAG-C is Pathogenic according to our data. Variant chr1-2406580-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 296273.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.814_815del	p.Leu272ValfsTer66	frameshift_variant	5/6	ENST00000447513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.814_815del	p.Leu272ValfsTer66	frameshift_variant	5/6	1	NM_002617.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250340 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135662

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461110 Hom.: 0 AF XY: 0.0000316 AC XY: 23 AN XY: 726892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74472

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger) Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PEX10 c.874_875delCT (p.Leu292ValfsTer66) variant causes a frameshift and is predicted to result in an elongation of the protein. The p.Leu292ValfsTer66 variant has been reported in at least four studies in which it is found in a homozygous state in at least 13 individuals with Zellweger syndrome and in an additional three alleles of unknown zygosity (Okumoto et al. 1998; Shimozawa et al. 2003; Krause et al. 2009; Ebberink et al. 2011). Eleven homozygotes for the p.Leu292ValfsTer66 variant shared a common haplotype, suggesting a founder effect for this variant in the Japanese population (Shimozawa et al. 2003). Control data are unavailable for the variant which is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. The frameshift caused by the p.Leu292ValfsTer66 variant interrupts a RING motif that is essential for protein function (Okumoto et al. 1998). In vivo complementation analyses in patient fibroblasts demonstrated that the p.Leu292ValfsTer66 variant results in a deficiency in PEX10 protein activity (Okumoto et al. 1998). Based on the potential impact of frameshift variants and the supporting evidence, the p.Leu292ValfsTer66 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2024	Published functional studies demonstrated a loss of PEX10 activity in an in vitro assay, suggesting a damaging effect (PMID: 10862081); Frameshift variant predicted to result in protein elongation, as the last 55 amino acids are replaced with 65 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Also known as 814-815delCT; This variant is associated with the following publications: (PMID: 10862081, 19142205, 9700193, 12794690, 34234304) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2017	- -

Peroxisome biogenesis disorder Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Common allele in the Japanese population, where it appears to have arisen once on an ancestral haplotype. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 30, 2016	Variant summary: The PEX10 c.874_875delCT (p.Leu292Valfs) variant causes a frameshift and is predicted to result in an elongation of the protein. Okumoto_1998 reported the variant to result in a protein entirely lacking the RING motif located immediately downstream of the mutated site, and multiple functional studies show lack of PEX10 activity as a result of the variant. This variant was found in 6/118582 control chromosomes at a frequency of 0.0000506, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX10 variant (0.001118). The variant was reported in numerous affected individual, and was reported as a Japanese founder mutation. Taken together, this variant is classified as pathogenic. -

Peroxisome biogenesis disorder 6B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Aug 16, 2016

- -

Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 14, 2022

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change creates a premature translational stop signal (p.Leu292Valfs*66) in the PEX10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the PEX10 protein. This variant is present in population databases (rs61752093, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Zellweger peroxisome deficiency syndrome (PMID: 9700193, 10862081, 12794690, 17041890, 19142205, 21031596). It is commonly reported in individuals of Japanese ancestry (PMID: 12794690). This variant is also known as c.814–815delCT and Leu272fs. ClinVar contains an entry for this variant (Variation ID: 296273). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PEX10 function (PMID: 9700193, 10862081). 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

- -

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: rs61752093; hg19: chr1-2338019;