12-7190262-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001351132.2(PEX5):c.-16-100G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 1,591,844 control chromosomes in the GnomAD database, including 926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (78 hom., cov: 32)
  • Exomes 𝑓: 0.032 (848 hom.)
• Consequence: PEX5 NM_001351132.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.121

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-7190262-G-A is Benign according to our data. Variant chr12-7190262-G-A is described in ClinVar as [Benign]. Clinvar id is 1291393.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0273 (4163/152268) while in subpopulation NFE AF= 0.0371 (2521/68000). AF 95% confidence interval is 0.0359. There are 78 homozygotes in gnomad4. There are 2146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX5	NM_001351132.2	c.-16-100G>A		intron_variant		ENST00000675855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX5	ENST00000675855.1	c.-16-100G>A		intron_variant			NM_001351132.2	A1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4166 AN: 152150 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0382

GnomAD4 exome AF: 0.0317 AC: 45601 AN: 1439576 Hom.: 848 Cov.: 30 AF XY: 0.0313 AC XY: 22446 AN XY: 716728

Gnomad4 AFR exome AF: 0.00529

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0313

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0564

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0297

GnomAD4 genome AF: 0.0273 AC: 4163 AN: 152268 Hom.: 78 Cov.: 32 AF XY: 0.0288 AC XY: 2146 AN XY: 74446

Gnomad4 AFR AF: 0.00570

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0641

Gnomad4 NFE AF: 0.0371

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0326 Hom.: 12

Bravo AF: 0.0239

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	10
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs74926388; hg19: chr12-7342858;