dbSNP rs267608190: PEX26:c.230+1G>A (chr22-18078607-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001127649.3(PEX26):c.230+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEX26
NM_001127649.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.69

Publications

0 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 12 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;

PP5

Variant 22-18078607-G-A is Pathogenic according to our data. Variant chr22-18078607-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2677688.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3 link	c.230+1G>A	splice_donor_variant, intron_variant	Intron 1 of 4	ENST00000399744.8	NP_001121121.1	Q7Z412-1A0A024R100
PEX26	NM_017929.6 link	c.230+1G>A	splice_donor_variant, intron_variant	Intron 2 of 5		NP_060399.1	Q7Z412-1A0A024R100
PEX26	NM_001199319.2 link	c.230+1G>A	splice_donor_variant, intron_variant	Intron 2 of 4		NP_001186248.1	Q7Z412-2Q7Z2D7A0A0S2Z5M7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8 link	c.230+1G>A		splice_donor_variant, intron_variant	Intron 1 of 4	1	NM_001127649.3	ENSP00000382648.4		Q7Z412-1
ENSG00000288683	ENST00000474897.6 link	n.230+1G>A		splice_donor_variant, intron_variant	Intron 2 of 8	5		ENSP00000434235.2		E9PRC5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718374

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:

39070

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:

0.00

AC:

AN:

1107022

Other (OTH)

AF:

0.00

AC:

AN:

59872

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 7A (Zellweger)

Pathogenic:1

Feb 16, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Benign

0.61

PhyloP100

2.7

GERP RS

5.3

PromoterAI

-0.15

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)

0.97

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.97

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over