1-2408761-T-C

Variant names:

• chr1-2408761-T-C
• rs2494598
• NM_002617.4:c.291A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002617.4(PEX10):​c.291A>G​(p.Thr97Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,613,626 control chromosomes in the GnomAD database, including 513,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T97T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42754 hom., cov: 33)
  • Exomes 𝑓: 0.80 (470883 hom.)
• Consequence: PEX10 NM_002617.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -6.52
• Publications: 27 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 1-2408761-T-C is Benign according to our data. Variant chr1-2408761-T-C is described in ClinVar as Benign. ClinVar VariationId is 129884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4	c.291A>G	p.Thr97Thr	synonymous_variant	Exon 3 of 6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7	c.291A>G	p.Thr97Thr	synonymous_variant	Exon 3 of 6	1	NM_002617.4	ENSP00000407922.2

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112937 AN: 151974 Hom.: 42746 Cov.: 33

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.741

GnomAD2 exomes AF: 0.773 AC: 193696 AN: 250422 AF XY: 0.776

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.718

Gnomad FIN exome AF: 0.808

Gnomad NFE exome AF: 0.811

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.801 AC: 1171196 AN: 1461534 Hom.: 470883 Cov.: 61 AF XY: 0.800 AC XY: 581559 AN XY: 727098

African (AFR) AF: 0.596 AC: 19953 AN: 33472

American (AMR) AF: 0.773 AC: 34556 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 21505 AN: 26120

East Asian (EAS) AF: 0.763 AC: 30284 AN: 39686

South Asian (SAS) AF: 0.728 AC: 62786 AN: 86246

European-Finnish (FIN) AF: 0.803 AC: 42797 AN: 53316

Middle Eastern (MID) AF: 0.707 AC: 4079 AN: 5768

European-Non Finnish (NFE) AF: 0.817 AC: 908139 AN: 1111848

Other (OTH) AF: 0.780 AC: 47097 AN: 60376

GnomAD4 genome AF: 0.743 AC: 112971 AN: 152092 Hom.: 42754 Cov.: 33 AF XY: 0.742 AC XY: 55167 AN XY: 74348

African (AFR) AF: 0.599 AC: 24812 AN: 41456

American (AMR) AF: 0.770 AC: 11780 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2869 AN: 3472

East Asian (EAS) AF: 0.725 AC: 3742 AN: 5162

South Asian (SAS) AF: 0.731 AC: 3526 AN: 4822

European-Finnish (FIN) AF: 0.804 AC: 8528 AN: 10606

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55189 AN: 67968

Other (OTH) AF: 0.734 AC: 1551 AN: 2112

Alfa AF: 0.785 Hom.: 23910

Bravo AF: 0.735

Asia WGS AF: 0.678 AC: 2359 AN: 3478

EpiCase AF: 0.807

EpiControl AF: 0.805

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Oct 09, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PEX10 c.291A>G (p.Thr97Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change located in the Pex, N-terminal domain(IPR006845) (InterPro). One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 212895/276368 control chromosomes (82611 homozygotes) (gnomAD) at a frequency of 0.7703316, indicating this variant is the major allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

not provided Benign:3

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 6A (Zellweger) Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 6B Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder, complementation group 7 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.017
DANN	Benign	0.23
PhyloP100		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2494598; hg19: chr1-2340200; COSMIC: COSV56581176; COSMIC: COSV56581176;