Genetic Variant PEX26:c.230+1G>C (chr22-18078607-G-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001127649.3(PEX26):c.230+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PEX26
NM_001127649.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PEX26	NM_001127649.3 link	c.230+1G>C	splice_donor_variant, intron_variant	Intron 1 of 4	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6 link	c.230+1G>C	splice_donor_variant, intron_variant	Intron 2 of 5		NP_060399.1
PEX26	NM_001199319.2 link	c.230+1G>C	splice_donor_variant, intron_variant	Intron 2 of 4		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8 link	c.230+1G>C		splice_donor_variant, intron_variant	Intron 1 of 4	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6 link	n.230+1G>C		splice_donor_variant, intron_variant	Intron 2 of 8	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445478

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33216

American (AMR)

AF:

0.00

AC:

AN:

43340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39072

South Asian (SAS)

AF:

0.00

AC:

AN:

84244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107022

Other (OTH)

AF:

0.00

AC:

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.0

.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

2.7

PROVEAN

Benign

0.0

.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.

Vest4

0.0

GERP RS

5.3

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over