chr22-18085172-C-T

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.728C>T(p.Ala243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,068 control chromosomes in the GnomAD database, including 17 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. A243A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 17 hom. )

Consequence

PEX26
NM_001127649.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.506

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=0.0070671737).

BP6

Variant 22-18085172-C-T is Benign according to our data. Variant chr22-18085172-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95879.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00153 (233/152284) while in subpopulation SAS AF = 0.0027 (13/4818). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3 link	c.728C>T	p.Ala243Val	missense_variant	Exon 4 of 5	ENST00000399744.8	NP_001121121.1	Q7Z412-1A0A024R100
PEX26	NM_017929.6 link	c.728C>T	p.Ala243Val	missense_variant	Exon 5 of 6		NP_060399.1	Q7Z412-1A0A024R100
PEX26	NM_001199319.2 link	c.667+1440C>T		intron_variant	Intron 4 of 4		NP_001186248.1	Q7Z412-2Q7Z2D7A0A0S2Z5M7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PEX26	ENST00000399744.8 link	c.728C>T	p.Ala243Val	missense_variant	Exon 4 of 5	1	NM_001127649.3	ENSP00000382648.4	Q7Z412-1
PEX26	ENST00000329627.11 link	c.728C>T	p.Ala243Val	missense_variant	Exon 5 of 6	1		ENSP00000331106.5	Q7Z412-1
ENSG00000288683	ENST00000474897.6 link	n.728C>T		non_coding_transcript_exon_variant	Exon 5 of 9	5		ENSP00000434235.2	E9PRC5
PEX26	ENST00000428061.2 link	c.667+1440C>T		intron_variant	Intron 3 of 3	1		ENSP00000412441.2	Q7Z412-2

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00263

AC:

662

AN:

251474

AF XY:

0.00280

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00201

AC:

2933

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

1545

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.00279

AC:

125

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

373

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00368

AC:

317

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00166

AC:

1844

AN:

1111930

Other (OTH)

AF:

0.00358

AC:

216

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

183

366

548

731

914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00153

AC:

233

AN:

152284

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41562

American (AMR)

AF:

0.00105

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00270

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00191

AC:

130

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00228

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00246

AC:

299

EpiCase

AF:

0.00436

EpiControl

AF:

0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 18, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PEX26: BP4, BS2 -

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. -

not specified

Benign:1

Apr 26, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 29, 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

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.68

.;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.51

PrimateAI

Benign

0.25

PROVEAN

Benign

0.39

N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T

Sift4G

Benign

0.89

T;T

Polyphen

0.037

B;B

Vest4

0.17

MVP

0.71

MPC

0.17

ClinPred

0.0012

GERP RS

-2.0

Varity_R

0.014

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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