rs724160002

Positions:

• chr1-2412501-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_002617.4(PEX10):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,210,336 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PEX10 NM_002617.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.10

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_002617.4 (PEX10) was described as [Likely_pathogenic] in ClinVar as 280002
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-2412501-A-G is Pathogenic according to our data. Variant chr1-2412501-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 162434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2412501-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX10	NM_002617.4	c.2T>C	p.Met1?	start_lost	1/6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7	c.2T>C	p.Met1?	start_lost	1/6	1	NM_002617.4	ENSP00000407922.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000107 AC: 13 AN: 1210336 Hom.: 0 Cov.: 31 AF XY: 0.00000508 AC XY: 3 AN XY: 590978

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 Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 24, 2017

- -

Peroxisome biogenesis disorder 6B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2010

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change affects the initiator methionine of the PEX10 mRNA. The next in-frame methionine is located at codon 145. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with peroxisomal biogenesis disorders (PMID: 20695019, 28320181). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162434). For these reasons, this variant has been classified as Pathogenic. -

Peroxisome biogenesis disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 21, 2023

Variant summary: PEX10 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in-frame methionine is at codon 145 (Exon 3). Other variants impacting the PEX10 start codon have been reported as pathogenic in ClinVar and HGMD (e.g., c.1A>G/p.M1V). Additionally, truncating variants downstream of the start-loss but upstream of the potential new start codon have been classified as pathogenic by our laboratory. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 26612 control chromosomes. c.2T>C has been reported in the literature in individuals affected with peroxisomal biogenesis disorders and ataxia (e.g., Regal_2010, Ebberink_2010) and has been shown to segregate with disease in related individuals (e.g., Yamashita_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that PEX10 was defective in fibroblasts from a compound heterozygous patient (with a null variant in trans; Regal_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.30	.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.010	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	D;B;.
Vest4		0.54
MutPred		0.59		Gain of glycosylation at M1 (P = 0.0074);Gain of glycosylation at M1 (P = 0.0074);Gain of glycosylation at M1 (P = 0.0074);
MVP		0.80
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.57

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: rs724160002; hg19: chr1-2343940;