rs759334733

Variant names:

• chr12-7209758-C-T
• rs759334733
• NM_001351132.2:c.1636C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001351132.2(PEX5):​c.1636C>T​(p.Arg546Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000089 in 1,584,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: PEX5 NM_001351132.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.78
• Publications: 2 publications found

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]

PEX5 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 2A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 2B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• rhizomelic chondrodysplasia punctata type 5

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351132.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	NM_001351132.2	MANE Select	c.1636C>T	p.Arg546Cys	missense	Exon 15 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.1681C>T	p.Arg561Cys	missense	Exon 15 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.1636C>T	p.Arg546Cys	missense	Exon 15 of 16	NP_001124497.1	A0A0S2Z4H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000675855.1	MANE Select	c.1636C>T	p.Arg546Cys	missense	Exon 15 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.1636C>T	p.Arg546Cys	missense	Exon 15 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266564.7	TSL:1	c.1612C>T	p.Arg538Cys	missense	Exon 14 of 15	ENSP00000266564.3	P50542-3

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 15 AN: 125860 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000820

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000239

Gnomad SAS AF: 0.000522

Gnomad FIN AF: 0.000240

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.000122

Gnomad OTH AF: 0.000600

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251468 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000864 AC: 126 AN: 1458762 Hom.: 0 Cov.: 34 AF XY: 0.0000799 AC XY: 58 AN XY: 725650

African (AFR) AF: 0.0000299 AC: 1 AN: 33390

American (AMR) AF: 0.0000897 AC: 4 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86230

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53152

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.0000964 AC: 107 AN: 1110054

Other (OTH) AF: 0.0000997 AC: 6 AN: 60164

GnomAD4 genome AF: 0.000119 AC: 15 AN: 125938 Hom.: 0 Cov.: 32 AF XY: 0.000147 AC XY: 9 AN XY: 61214

African (AFR) AF: 0.00 AC: 0 AN: 34154

American (AMR) AF: 0.0000819 AC: 1 AN: 12216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2952

East Asian (EAS) AF: 0.000239 AC: 1 AN: 4182

South Asian (SAS) AF: 0.000522 AC: 2 AN: 3828

European-Finnish (FIN) AF: 0.000240 AC: 2 AN: 8318

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.000122 AC: 7 AN: 57566

Other (OTH) AF: 0.000591 AC: 1 AN: 1692

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	Peroxisome biogenesis disorder 2A (Zellweger) (1)
-	1	-	Peroxisome biogenesis disorder 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
Polyphen		0.66	P
Vest4		0.80
MutPred		0.56		Loss of disorder (P = 0.0371)
MVP		0.75
MPC		0.40
ClinPred		0.62	D
GERP RS		5.4
Varity_R		0.63
gMVP		0.58
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs759334733; hg19: chr12-7362354; COSMIC: COSV104561836; COSMIC: COSV104561836;