rs150895887

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_001127649.3(PEX26):c.130C>T(p.Leu44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,571,354 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L44P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0064 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 12 hom. )

Consequence

PEX26
NM_001127649.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.139

Publications

3 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 -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-18078507-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3768062.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.012090355).

BP6

Variant 22-18078506-C-T is Benign according to our data. Variant chr22-18078506-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195337.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00641 (976/152244) while in subpopulation AFR AF = 0.0163 (678/41568). AF 95% confidence interval is 0.0153. There are 5 homozygotes in GnomAd4. There are 456 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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
PEX26	NM_001127649.3 link	c.130C>T	p.Leu44Phe	missense_variant	Exon 1 of 5	ENST00000399744.8	NP_001121121.1	Q7Z412-1A0A024R100
PEX26	NM_017929.6 link	c.130C>T	p.Leu44Phe	missense_variant	Exon 2 of 6		NP_060399.1	Q7Z412-1A0A024R100
PEX26	NM_001199319.2 link	c.130C>T	p.Leu44Phe	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.130C>T	p.Leu44Phe	missense_variant	Exon 1 of 5	1	NM_001127649.3	ENSP00000382648.4		Q7Z412-1
ENSG00000288683	ENST00000474897.6 link	n.130C>T		non_coding_transcript_exon_variant	Exon 2 of 9	5		ENSP00000434235.2		E9PRC5

Frequencies

GnomAD3 genomes

AF:

0.00639

AC:

972

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00300

AC:

521

AN:

173610

AF XY:

0.00258

show subpopulations

Gnomad AFR exome

AF:

0.0161

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.00642

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000989

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00168

AC:

2386

AN:

1419110

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1119

AN XY:

703052

show subpopulations

African (AFR)

AF:

0.0167

AC:

547

AN:

32712

American (AMR)

AF:

0.00750

AC:

291

AN:

38806

Ashkenazi Jewish (ASJ)

AF:

0.00656

AC:

167

AN:

25448

East Asian (EAS)

AF:

0.0000266

AC:

AN:

37598

South Asian (SAS)

AF:

0.0000728

AC:

AN:

82414

European-Finnish (FIN)

AF:

0.0000228

AC:

AN:

43854

Middle Eastern (MID)

AF:

0.00656

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.000993

AC:

1086

AN:

1093668

Other (OTH)

AF:

0.00424

AC:

250

AN:

58972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

144

287

431

574

718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00641

AC:

976

AN:

152244

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

456

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0163

AC:

678

AN:

41568

American (AMR)

AF:

0.0112

AC:

172

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

67998

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

129

172

215

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:

0.00266

Hom.:

Bravo

AF:

0.00744

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00699

AC:

ESP6500EA

AF:

0.00127

AC:

ExAC

AF:

0.00166

AC:

192

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 23, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Sep 29, 2015

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1Benign:1

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 04, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 7A (Zellweger)

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.23

.;T;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.62

T;.;T;.

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

-0.096

MutationAssessor

Benign

1.3

L;L;L;L

PhyloP100

0.14

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

.;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.13

.;T;T;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.015

.;B;B;.

Vest4

0.27

MVP

0.65

MPC

0.20

ClinPred

0.0081

GERP RS

0.74

PromoterAI

0.31

Neutral

(source)

Varity_R

0.093

gMVP

0.32

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