ENST00000420616:c.-332G>A

Variant names:

• chr12-7189901-G-A
• rs146875386
• ENST00000420616:c.-332G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000420616(PEX5):​c.-332G>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 0.00111 in 1,418,742 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (36 hom.)
• Consequence: PEX5 ENST00000420616 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.190

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 12-7189901-G-A is Benign according to our data. Variant chr12-7189901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 310410.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000827 (126/152328) while in subpopulation EAS AF= 0.0211 (109/5174). AF 95% confidence interval is 0.0179. There are 2 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.-17+151G>A		intron_variant	Intron 1 of 15	ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.-17+151G>A		intron_variant	Intron 1 of 15		NM_001351132.2	ENSP00000502374.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00151 AC: 69 AN: 45774 Hom.: 0 AF XY: 0.00131 AC XY: 34 AN XY: 25860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000392

Gnomad EAS exome AF: 0.0154

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00115 AC: 1452 AN: 1266414 Hom.: 36 Cov.: 30 AF XY: 0.00110 AC XY: 678 AN XY: 615080

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000354

Gnomad4 EAS exome AF: 0.0410

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000609

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0211

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000495

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 2A (Zellweger) Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.5
DANN	Benign	0.92
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2

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

LitVar

Other links and lift over

dbSNP: rs146875386; hg19: chr12-7342497;