1-2408761-T-C

Position:

• chr1-2408761-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002617.4(PEX10):​c.291A>G​(p.Thr97=) 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:10
• Conservation: PhyloP100: -6.52

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 Benign. Variant got -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 id is 129884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2408761-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PEX10	NM_002617.4	c.291A>G	p.Thr97=	synonymous_variant	3/6	ENST00000447513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.291A>G	p.Thr97=	synonymous_variant	3/6	1	NM_002617.4	P4

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

GnomAD3 exomes AF: 0.773 AC: 193696 AN: 250422 Hom.: 75406 AF XY: 0.776 AC XY: 105260 AN XY: 135608

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 SAS exome AF: 0.725

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

Gnomad4 AFR exome AF: 0.596

Gnomad4 AMR exome AF: 0.773

Gnomad4 ASJ exome AF: 0.823

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.728

Gnomad4 FIN exome AF: 0.803

Gnomad4 NFE exome AF: 0.817

Gnomad4 OTH exome AF: 0.780

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

Gnomad4 AFR AF: 0.599

Gnomad4 AMR AF: 0.770

Gnomad4 ASJ AF: 0.826

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.731

Gnomad4 FIN AF: 0.804

Gnomad4 NFE AF: 0.812

Gnomad4 OTH AF: 0.734

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2017	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. -

Peroxisome biogenesis disorder 6A (Zellweger) Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -

Peroxisome biogenesis disorder 6B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Peroxisome biogenesis disorder, complementation group 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Zellweger spectrum disorders Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.017
DANN	Benign	0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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