1-2412501-A-G

Variant names:

• chr1-2412501-A-G
• rs724160002
• NM_002617.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 6A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive ataxia due to PEX10 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 145 codons. Genomic position: 2408619. Lost 0.441 part of the original CDS.
• PS1: Another start lost variant in NM_002617.4 (PEX10) was described as [Likely_pathogenic] in ClinVar
• 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 VariationId is 162434.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	c.2T>C	p.Met1?	start_lost	Exon 1 of 6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7	c.2T>C	p.Met1?	start_lost	Exon 1 of 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

African (AFR) AF: 0.00 AC: 0 AN: 24164

American (AMR) AF: 0.00 AC: 0 AN: 13718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18018

East Asian (EAS) AF: 0.00 AC: 0 AN: 26708

South Asian (SAS) AF: 0.00 AC: 0 AN: 53466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3422

European-Non Finnish (NFE) AF: 0.0000131 AC: 13 AN: 992054

Other (OTH) AF: 0.00 AC: 0 AN: 49346

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

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

Feb 24, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Peroxisome biogenesis disorder 6B Pathogenic:1

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		3.1
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
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.57
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs724160002; hg19: chr1-2343940;