rs542096066

Variant names:

• chr12-7190088-G-A
• rs542096066
• ENST00000420616.6:c.-145G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001131025.2(PEX5):​c.-145G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,491,518 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (6 hom.)
• Consequence: PEX5 NM_001131025.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00189 (288/152118) while in subpopulation NFE AF = 0.0031 (211/67970). AF 95% confidence interval is 0.00276. There are 0 homozygotes in GnomAd4. There are 129 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
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131025.2. 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.-16-274G>A		intron	N/A	NP_001338061.1	P50542-1
	PEX5	NM_001131025.2		c.-145G>A		5_prime_UTR	Exon 1 of 16	NP_001124497.1	A0A0S2Z4H1
	PEX5	NM_001131026.2		c.-145G>A		5_prime_UTR	Exon 2 of 18	NP_001124498.1	P50542-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000420616.6	TSL:1	c.-145G>A		5_prime_UTR	Exon 1 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000675855.1	MANE Select	c.-16-274G>A		intron	N/A	ENSP00000502374.1	P50542-1
	PEX5	ENST00000266563.9	TSL:1	c.-16-274G>A		intron	N/A	ENSP00000266563.5	P50542-2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00289 AC: 3876 AN: 1339400 Hom.: 6 Cov.: 32 AF XY: 0.00290 AC XY: 1916 AN XY: 659834

African (AFR) AF: 0.000659 AC: 19 AN: 28836

American (AMR) AF: 0.000798 AC: 17 AN: 21300

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 44 AN: 22670

East Asian (EAS) AF: 0.00 AC: 0 AN: 35436

South Asian (SAS) AF: 0.00239 AC: 173 AN: 72260

European-Finnish (FIN) AF: 0.000485 AC: 16 AN: 32964

Middle Eastern (MID) AF: 0.00388 AC: 18 AN: 4638

European-Non Finnish (NFE) AF: 0.00325 AC: 3465 AN: 1065460

Other (OTH) AF: 0.00222 AC: 124 AN: 55836

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74354

African (AFR) AF: 0.000482 AC: 20 AN: 41524

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5128

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 67970

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		1.5
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs542096066; hg19: chr12-7342684;