22-18079996-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001127649.3(PEX26):c.353C>G(p.Pro118Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PEX26
NM_001127649.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 6.34

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 links:

ENSG00000288683 (HGNC:):

ENSG00000288683 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 22-18079996-C-G is Pathogenic according to our data. Variant chr22-18079996-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449363.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr22-18079996-C-G is described in Lovd as [Pathogenic]. Variant chr22-18079996-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3 link	c.353C>G	p.Pro118Arg	missense_variant	Exon 2 of 5	ENST00000399744.8	NP_001121121.1	Q7Z412-1A0A024R100
PEX26	NM_017929.6 link	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 6		NP_060399.1	Q7Z412-1A0A024R100
PEX26	NM_001199319.2 link	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 5		NP_001186248.1	Q7Z412-2Q7Z2D7A0A0S2Z5M7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PEX26	ENST00000399744.8 link	c.353C>G	p.Pro118Arg	missense_variant	Exon 2 of 5	1	NM_001127649.3	ENSP00000382648.4	Q7Z412-1
PEX26	ENST00000329627.11 link	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 6	1		ENSP00000331106.5	Q7Z412-1
PEX26	ENST00000428061.2 link	c.353C>G	p.Pro118Arg	missense_variant	Exon 2 of 4	1		ENSP00000412441.2	Q7Z412-2
ENSG00000288683	ENST00000474897.6 link	n.353C>G		non_coding_transcript_exon_variant	Exon 3 of 9	5		ENSP00000434235.2	E9PRC5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251462

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 7A (Zellweger)

Pathogenic:1

Jun 28, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jun 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect (PMID: 34804114); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30446579, 19105186, 35805150, 34804114, 15542397, 38323187, 32140910) -

not specified

Uncertain:1

Aug 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PEX26 c.353C>G (p.Pro118Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251462 control chromosomes. c.353C>G has been reported in the literature in a homozygous and a compound heterozygous individuals affected with Zellweger Syndrome (Steinberg_2004, Brkl-Ycel_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32140910, 15542397). ClinVar contains an entry for this variant (Variation ID: 449363). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 118 of the PEX26 protein (p.Pro118Arg). This variant is present in population databases (rs61752135, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of PEX26-related conditions (PMID: 15542397, 32140910). ClinVar contains an entry for this variant (Variation ID: 449363). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;.;D;.

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.6

M;M;M;M

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.4

.;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.026

.;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.75

MutPred

0.92

Loss of catalytic residue at P117 (P = 0.0107);Loss of catalytic residue at P117 (P = 0.0107);Loss of catalytic residue at P117 (P = 0.0107);Loss of catalytic residue at P117 (P = 0.0107);

MVP

0.93

MPC

0.70

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over