chr12-7210117-G-A

Variant names:

• chr12-7210117-G-A
• rs146567534
• NM_001351132.2:c.1814G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BS1_Supporting

The NM_001351132.2(PEX5):​c.1814G>A​(p.Ser605Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000549 in 1,614,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S605S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: PEX5 NM_001351132.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 B:1
• Conservation: PhyloP100: 4.07
• Publications: 8 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001351132.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.057721555).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000473 (72/152366) while in subpopulation NFE AF = 0.000823 (56/68032). AF 95% confidence interval is 0.000651. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1814G>A	p.Ser605Asn	missense	Exon 16 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.1859G>A	p.Ser620Asn	missense	Exon 16 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.1814G>A	p.Ser605Asn	missense	Exon 16 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.1814G>A	p.Ser605Asn	missense	Exon 16 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.1814G>A	p.Ser605Asn	missense	Exon 16 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266564.7	TSL:1	c.1790G>A	p.Ser597Asn	missense	Exon 15 of 15	ENSP00000266564.3	P50542-3

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000537 AC: 135 AN: 251354 AF XY: 0.000545

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000557 AC: 814 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.000576 AC XY: 419 AN XY: 727248

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000625 AC: 695 AN: 1112010

Other (OTH) AF: 0.000679 AC: 41 AN: 60396

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74522

African (AFR) AF: 0.000120 AC: 5 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000928 Hom.: 6

Bravo AF: 0.000461

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.00115

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Peroxisome biogenesis disorder 2A (Zellweger) (1)
-	1	-	Peroxisome biogenesis disorder 2B (1)
-	1	-	Peroxisome biogenesis disorder 2B;C3550273:Peroxisome biogenesis disorder 2A (Zellweger);C4225237:Rhizomelic chondrodysplasia punctata type 5 (1)
-	-	1	PEX5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.058	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.73
MPC		0.25
ClinPred		0.077	T
GERP RS		4.2
Varity_R		0.89
gMVP		0.67
Mutation Taster		=54/46	polymorphism

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: rs146567534; hg19: chr12-7362713; COSMIC: COSV99030497; COSMIC: COSV99030497;