12-7190040-T-A

Position:

• chr12-7190040-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000420616.6(PEX5):​c.-193T>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 0.0996 in 1,502,774 control chromosomes in the GnomAD database, including 8,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (651 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7854 hom.)
• Consequence: PEX5 ENST00000420616.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-7190040-T-A is Benign according to our data. Variant chr12-7190040-T-A is described in ClinVar as [Benign]. Clinvar id is 310415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.-17+290T>A		intron_variant		ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.-17+290T>A		intron_variant			NM_001351132.2	ENSP00000502374	A1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11793 AN: 152098 Hom.: 653 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0864

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.102 AC: 137873 AN: 1350558 Hom.: 7854 Cov.: 33 AF XY: 0.101 AC XY: 67279 AN XY: 666326

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.0741

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.000309

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.0749

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.0991

GnomAD4 genome AF: 0.0774 AC: 11788 AN: 152216 Hom.: 651 Cov.: 32 AF XY: 0.0744 AC XY: 5536 AN XY: 74434

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.0863

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.0701

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0996 Hom.: 108

Bravo AF: 0.0786

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Peroxisome biogenesis disorder 2A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.75
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs113752912; hg19: chr12-7342636;