rs61752138

Variant names:

• chr12-7209700-T-A
• NM_001351132.2:c.1578T>A

Your query was ambiguous. Multiple possible variants found:

• chr12-7209700-T-A
• chr12-7209700-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001351132.2(PEX5):​c.1578T>A​(p.Asn526Lys) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PEX5 NM_001351132.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.891

Genes affected

PEX5 (HGNC:9719): (peroxisomal biogenesis factor 5) The product of this gene binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of neonatal adrenoleukodystrophy (NALD), a cause of Zellweger syndrome (ZWS) as well as may be a cause of infantile Refsum disease (IRD). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 12-7209700-T-A is Pathogenic according to our data. Variant chr12-7209700-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2978647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.1578T>A	p.Asn526Lys	missense_variant	Exon 15 of 16	ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.1578T>A	p.Asn526Lys	missense_variant	Exon 15 of 16		NM_001351132.2	ENSP00000502374.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 2B Pathogenic:1

May 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 526 of the PEX5 protein (p.Asn526Lys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PEX5 function (PMID: 10462504, 17532062). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX5 protein function. This variant is also known as Asn489Lys. This missense change has been observed in individuals with Zellweger syndrome spectrum (PMID: 10462504, 20681997, 30561787, 34645488). This variant is not present in population databases (gnomAD no frequency). -

Peroxisome biogenesis disorder Pathogenic:1

Apr 25, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PEX5 c.1578T>A (p.Asn526Lys) 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 was absent in 251374 control chromosomes. To our knowledge, no occurrence of c.1578T>A in individuals affected with Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum has been reported. Experimental studies show that p.Asn526Lys abolishes the PTS1-binding capacity and import function of Pex5p (e.g. Carvalho_2007, Shimozawa_1999). This variant is also known as Asn489Lys. A different nucleotide change, c.1578T>G resulting in the same amino acid change is known to be pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 17532062, 10462504). ClinVar contains an entry for this variant (Variation ID: 2978647). Based on the evidence outlined above, the variant was classified as pathogenic. -

Peroxisome biogenesis disorder 2B;C3550273:Peroxisome biogenesis disorder 2A (Zellweger);C4225237:Rhizomelic chondrodysplasia punctata type 5 Pathogenic:1

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.;D;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.7	H;.;.;H;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D
Vest4		0.98
MutPred		0.74		.;.;.;.;Gain of catalytic residue at L544 (P = 2e-04);.;
MVP		0.84
MPC		1.0
ClinPred		1.0	D
GERP RS		0.38
Varity_R		0.97
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7362296;