Variant 1-2406580-CAG-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 0.566

Variant links:

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]

PEX10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.814_815del	p.Leu272ValfsTer66	frameshift_variant	5/6	1	NM_002617.4	P4	O60683-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

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:

AN:

250340

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135662

show subpopulations

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:

AN:

1461110

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

726892

show subpopulations

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:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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:1Other: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‚Äì815delCT 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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over