rs2135875571

Variant names:

• chr12-7190378-A-G
• rs2135875571
• NM_001351132.2:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001351132.2(PEX5):​c.1A>G​(p.Met1?) variant causes a start lost change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX5 NM_001351132.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 0 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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 codons. Genomic position: 7190384. Lost 0.004 part of the original CDS.
• 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.1A>G	p.Met1?	start_lost	Exon 2 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.1A>G	p.Met1?	start_lost	Exon 2 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.1A>G	p.Met1?	start_lost	Exon 2 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.1A>G	p.Met1?	start_lost	Exon 2 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 2 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266564.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000266564.3	P50542-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.43	D
PhyloP100		4.7
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.52		Gain of catalytic residue at M24 (P = 0)
MVP		0.83
ClinPred		1.0	D
GERP RS		2.4
PromoterAI		0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.84
Mutation Taster		=34/166	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: rs2135875571; hg19: chr12-7342974;