dbSNP rs61750435: PEX10:p.Leu236AlafsTer103 (chr1-2406791-C-CT) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_002617.4(PEX10):c.704dupA(p.Leu236AlafsTer103) variant causes a frameshift change. The variant allele was found at a frequency of 0.00014 in 1,610,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PEX10
NM_002617.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 5.03

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 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 1-2406791-C-CT is Pathogenic according to our data. Variant chr1-2406791-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 6774.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
PEX10	NM_002617.4 link	c.704dupA	p.Leu236AlafsTer103	frameshift_variant	Exon 4 of 6	ENST00000447513.7	NP_002608.1	O60683-1A0A024R068

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7 link	c.704dupA	p.Leu236AlafsTer103	frameshift_variant	Exon 4 of 6	1	NM_002617.4	ENSP00000407922.2		O60683-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000206

AC:

AN:

242276

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131988

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000458

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1458430

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

725322

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000187

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger)

Pathogenic:3

Jul 22, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 6B

Pathogenic:2

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 22, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Oct 20, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation as the last 91 amino acids are replaced with 102 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21031596, 10862081, 17702006, 20695019) -

Nov 29, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PEX10-related disorder

Pathogenic:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PEX10 c.764dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu256Alafs*103). This variant was found in a compound heterozygous state in three patients affected by peroxisomal biogenesis disorders (PBD) (Warren et al. 2000. PubMed ID: 10862081; Steinberg et al. 2004. PubMed ID: 15542397; Régal et al. 2010. PubMed ID: 20695019). This variant is reported in 0.0056% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in PEX10 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder, complementation group 7

Pathogenic:1

Nov 13, 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.Leu256Alafs*103) in the PEX10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the PEX10 protein. This variant is present in population databases (rs61750435, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Zellweger syndrome spectrum (PMID: 10862081, 17702006, 19105186, 20695019, 21031596). This variant is also known as c.704dupA, c.764_765insA or p.L256fsX102. ClinVar contains an entry for this variant (Variation ID: 6774). 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 PEX10 function (PMID: 10862081, 20695019). For these reasons, this variant has been classified as Pathogenic. -

Peroxisome biogenesis disorder

Pathogenic:1

Sep 14, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PEX10 c.764dupA (p.Leu256AlafsX92+) variant causes a frameshift and is predicted to result in an elongation of the protein. One frameshift/elongation variant in PEX10 has been classified as pathogenic by our laboratory (e.g. c.874_875delCT, p.Leu292fsX55+). One in silico tool predicts a damaging outcome for this variant. One functional study showed less than 50% relative rescue activity compared to the wild type (Warren_2000). The variant was found in the control population dataset of ExAC in 2/93566 control chromosomes at a frequency of 0.0000214, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX10 variant (0.001118). This variant was reported in multiple Zellweger syndrome patients, in homozygotes and heterozygotes, including one case of uniparental disomy (Ebberink_2010, Turner_PEX10). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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