1-2406576-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_002617.4(PEX10):c.820A>G(p.Thr274Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,202 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T274I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 42 hom., cov: 33)

Exomes 𝑓: 0.023 ( 465 hom. )

Consequence

PEX10
NM_002617.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.96

Publications

17 publications found

Variant links:

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

PEX10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_002617.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0106090605).

BP6

Variant 1-2406576-T-C is Benign according to our data. Variant chr1-2406576-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2850/152162) while in subpopulation NFE AF = 0.0264 (1793/67986). AF 95% confidence interval is 0.0254. There are 42 homozygotes in GnomAd4. There are 1323 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4 link	c.820A>G	p.Thr274Ala	missense_variant	Exon 5 of 6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7 link	c.820A>G	p.Thr274Ala	missense_variant	Exon 5 of 6	1	NM_002617.4	ENSP00000407922.2

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2851

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0842

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00975

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0264

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0203

AC:

5069

AN:

250264

AF XY:

0.0205

show subpopulations

Gnomad AFR exome

AF:

0.00428

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0814

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0231

AC:

33805

AN:

1461040

Hom.:

465

Cov.:

AF XY:

0.0230

AC XY:

16719

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.00349

AC:

117

AN:

33478

American (AMR)

AF:

0.0142

AC:

633

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0824

AC:

2152

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0100

AC:

865

AN:

86252

European-Finnish (FIN)

AF:

0.0140

AC:

739

AN:

52656

Middle Eastern (MID)

AF:

0.0260

AC:

150

AN:

5766

European-Non Finnish (NFE)

AF:

0.0248

AC:

27590

AN:

1111954

Other (OTH)

AF:

0.0258

AC:

1557

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2085

4170

6256

8341

10426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1030

2060

3090

4120

5150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0187

AC:

2850

AN:

152162

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1323

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00472

AC:

196

AN:

41522

American (AMR)

AF:

0.0186

AC:

285

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0842

AC:

292

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00976

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0149

AC:

158

AN:

10604

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0264

AC:

1793

AN:

67986

Other (OTH)

AF:

0.0289

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

154

309

463

618

772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0247

Hom.:

Bravo

AF:

0.0182

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0286

AC:

246

ExAC

AF:

0.0188

AC:

2277

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0310

EpiControl

AF:

0.0271

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 272/13006=2%

Nov 23, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 01, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15542397, 27535533, 19127411)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Peroxisome biogenesis disorder 6A (Zellweger)

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Thr294Ala variant in PEX10 has been identified in cis with a frameshift mutation and in an individual with Zellweger syndrome (PMID: 19127411). This variant has been identified in >2% of European (non-Finnish) chromosomes and 36 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Zellweger syndrome.

Zellweger spectrum disorders

Benign:1

Nov 26, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Peroxisome biogenesis disorder, complementation group 7

Benign:1

Feb 03, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

3.0

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.16

T;T;T

Vest4

0.47

ClinPred

0.020

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.44

Mutation Taster

=82/18

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over