rs116873137

Positions:

• chr12-7209853-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001351132.2(PEX5):​c.1718+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,016 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.017 (268 hom.)
• Consequence: PEX5 NM_001351132.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.89

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=-0.84).
• BP6: Variant 12-7209853-A-G is Benign according to our data. Variant chr12-7209853-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1633/152288) while in subpopulation NFE AF= 0.0185 (1255/68020). AF 95% confidence interval is 0.0176. There are 13 homozygotes in gnomad4. There are 756 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX5	NM_001351132.2	c.1718+13A>G		intron_variant		ENST00000675855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX5	ENST00000675855.1	c.1718+13A>G		intron_variant			NM_001351132.2	A1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1633 AN: 152170 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0104 AC: 2621 AN: 251348 Hom.: 26 AF XY: 0.0106 AC XY: 1434 AN XY: 135878

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0168 AC: 24506 AN: 1461728 Hom.: 268 Cov.: 34 AF XY: 0.0164 AC XY: 11897 AN XY: 727154

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00758

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0107 AC: 1633 AN: 152288 Hom.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 756 AN XY: 74466

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0124 Hom.: 3

Bravo AF: 0.0113

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Peroxisome biogenesis disorder 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2018

- -

Peroxisome biogenesis disorder 2A (Zellweger) Benign:1

Likely 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 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	-0.84
CADD	Benign	0.0050
DANN	Benign	0.46

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: rs116873137; hg19: chr12-7362449;