rs369965266

chr1-2408700-G-A

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.352C>T(p.Gln118Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,126 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX10 NM_002617.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.84

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-2408700-G-A is Pathogenic according to our data. Variant chr1-2408700-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371748.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.352C>T	p.Gln118Ter	stop_gained	3/6	ENST00000447513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.352C>T	p.Gln118Ter	stop_gained	3/6	1	NM_002617.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726904

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Oct 21, 2016

- -

Peroxisome biogenesis disorder 6B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Oct 21, 2016

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Gln118*) 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 variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum disorder (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 371748). For these reasons, this variant has been classified as Pathogenic. -

Peroxisome biogenesis disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 21, 2022

Variant summary: PEX10 c.352C>T (p.Gln118X) 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 was absent in 247864 control chromosomes (gnomAD). c.352C>T has been reported in the literature in an individual (homozygous) affected with Zellweger Syndrome Spectrum disorder (Ebberink_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.80
GERP RS		4.9

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

Other links and lift over

dbSNP: rs369965266; hg19: chr1-2340139;