rs139345520

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002617.4(PEX10):c.685G>C(p.Val229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,610,988 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. V229A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0062 ( 5 hom., cov: 34)

Exomes 𝑓: 0.00061 ( 10 hom. )

Consequence

PEX10
NM_002617.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.780

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011860877).

BP6

Variant 1-2406811-C-G is Benign according to our data. Variant chr1-2406811-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0062 (944/152338) while in subpopulation AFR AF = 0.0215 (893/41580). AF 95% confidence interval is 0.0203. There are 5 homozygotes in GnomAd4. There are 464 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4 link	c.685G>C	p.Val229Leu	missense_variant	Exon 4 of 6	ENST00000447513.7	NP_002608.1	O60683-1A0A024R068

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7 link	c.685G>C	p.Val229Leu	missense_variant	Exon 4 of 6	1	NM_002617.4	ENSP00000407922.2		O60683-1

Frequencies

GnomAD3 genomes

AF:

0.00619

AC:

943

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00155

AC:

377

AN:

242962

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.0218

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000730

Gnomad OTH exome

AF:

0.000677

GnomAD4 exome

AF:

0.000608

AC:

887

AN:

1458650

Hom.:

Cov.:

AF XY:

0.000521

AC XY:

378

AN XY:

725432

show subpopulations

African (AFR)

AF:

0.0218

AC:

728

AN:

33442

American (AMR)

AF:

0.00108

AC:

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52250

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111040

Other (OTH)

AF:

0.00133

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00620

AC:

944

AN:

152338

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0215

AC:

893

AN:

41580

American (AMR)

AF:

0.00281

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00174

Hom.:

Bravo

AF:

0.00700

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00171

AC:

207

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Peroxisome biogenesis disorder 6A (Zellweger)

Benign:1

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. -

Peroxisome biogenesis disorder, complementation group 7

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Zellweger spectrum disorders

Benign:1

Oct 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.1

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.084

.;T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.40

.;N;.

PhyloP100

0.78

PrimateAI

Benign

0.34

PROVEAN

Benign

0.030

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.66

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.13

MutPred

0.59

.;Loss of MoRF binding (P = 0.0901);Loss of MoRF binding (P = 0.0901);

MVP

0.41

MPC

0.092

ClinPred

0.00095

GERP RS

2.5

Varity_R

0.072

gMVP

0.46

Mutation Taster

=100/0

polymorphism

(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

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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