12-7189747-C-G

Position:

• chr12-7189747-C-G

Variant summary

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

The NM_001351132.2(PEX5):​c.-20C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 427,362 control chromosomes in the GnomAD database, including 55,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15767 hom., cov: 32)
  • Exomes 𝑓: 0.53 (40029 hom.)
• Consequence: PEX5 NM_001351132.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.226

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=-0.82).
• BP6: Variant 12-7189747-C-G is Benign according to our data. Variant chr12-7189747-C-G is described in ClinVar as [Benign]. Clinvar id is 310406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.-20C>G		5_prime_UTR_variant	1/16	ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.-20C>G		5_prime_UTR_variant	1/16		NM_001351132.2	ENSP00000502374	A1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64951 AN: 151756 Hom.: 15755 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.466

GnomAD4 exome AF: 0.531 AC: 146303 AN: 275496 Hom.: 40029 Cov.: 4 AF XY: 0.532 AC XY: 74025 AN XY: 139198

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.527

Gnomad4 EAS exome AF: 0.422

Gnomad4 SAS exome AF: 0.579

Gnomad4 FIN exome AF: 0.463

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.428 AC: 64978 AN: 151866 Hom.: 15767 Cov.: 32 AF XY: 0.428 AC XY: 31733 AN XY: 74210

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.605

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.404

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.462

Alfa AF: 0.321 Hom.: 854

Bravo AF: 0.431

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

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 13, 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	-0.82
CADD	Benign	8.9
DANN	Benign	0.39

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: rs12227917; hg19: chr12-7342343;