rs201884779

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127649.3(PEX26):c.200A>G(p.Asn67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,599,366 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N67N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 7 hom. )

Consequence

PEX26
NM_001127649.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -0.923

Publications

6 publications found

Variant links:

Genes affected

PEX26 (HGNC:22965): (peroxisomal biogenesis factor 26) This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]

PEX26 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 7A (Zellweger)
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
peroxisome biogenesis disorder 7B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX26 links:

ENSG00000288683 (HGNC:):

ENSG00000288683 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043507814).

BP6

Variant 22-18078576-A-G is Benign according to our data. Variant chr22-18078576-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288461.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (267/152190) while in subpopulation NFE AF = 0.00315 (214/67980). AF 95% confidence interval is 0.0028. There are 1 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3 link	c.200A>G	p.Asn67Ser	missense_variant	Exon 1 of 5	ENST00000399744.8	NP_001121121.1	Q7Z412-1A0A024R100
PEX26	NM_017929.6 link	c.200A>G	p.Asn67Ser	missense_variant	Exon 2 of 6		NP_060399.1	Q7Z412-1A0A024R100
PEX26	NM_001199319.2 link	c.200A>G	p.Asn67Ser	missense_variant	Exon 2 of 5		NP_001186248.1	Q7Z412-2Q7Z2D7A0A0S2Z5M7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8 link	c.200A>G	p.Asn67Ser	missense_variant	Exon 1 of 5	1	NM_001127649.3	ENSP00000382648.4		Q7Z412-1
ENSG00000288683	ENST00000474897.6 link	n.200A>G		non_coding_transcript_exon_variant	Exon 2 of 9	5		ENSP00000434235.2		E9PRC5

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00136

AC:

294

AN:

216380

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000818

Gnomad AMR exome

AF:

0.00135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000191

Gnomad NFE exome

AF:

0.00221

Gnomad OTH exome

AF:

0.000729

GnomAD4 exome

AF:

0.00277

AC:

4002

AN:

1447176

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1952

AN XY:

719300

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

33260

American (AMR)

AF:

0.00140

AC:

AN:

43418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.000912

AC:

AN:

84390

European-Finnish (FIN)

AF:

0.000333

AC:

AN:

48006

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00336

AC:

3724

AN:

1107468

Other (OTH)

AF:

0.00167

AC:

100

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

227

453

680

906

1133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00175

AC:

267

AN:

152190

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

112

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41548

American (AMR)

AF:

0.000981

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00315

AC:

214

AN:

67980

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00171

Hom.:

Bravo

AF:

0.00180

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00159

AC:

ExAC

AF:

0.000991

AC:

118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PEX26: BP4 -

Sep 15, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 25, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The N67S variant in the PEX26 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 75/25,018 alleles (0.3%) from individuals of non-Finnish European background in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). The N67S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. As there is not enough information currently available to determine if this variant is pathogenic or benign, we interpret N67S as a variant of uncertain significance. -

Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger)

Uncertain:1Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 7A (Zellweger)

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PEX26-related disorder

Benign:1

Feb 04, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.33

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.12

.;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.65

T;.;T;.

M_CAP

Benign

0.061

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

-0.67

N;N;N;N

PhyloP100

-0.92

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.14

.;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.70

.;T;T;T

Sift4G

Benign

0.67

T;T;T;T

Polyphen

0.0010

.;B;B;.

Vest4

0.065

MVP

0.51

MPC

0.13

ClinPred

0.0031

GERP RS

-3.6

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.094

Mutation Taster

=98/2

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