17-35575265-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000286.3(PEX12):c.*517A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 159,382 control chromosomes in the GnomAD database, including 12,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (11584 hom., cov: 31)
  • Exomes 𝑓: 0.38 (607 hom.)
• Consequence: PEX12 NM_000286.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.212

Genes affected

PEX12 (HGNC:8854): (peroxisomal biogenesis factor 12) This gene belongs to the peroxin-12 family. 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 Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-35575265-T-C is Benign according to our data. Variant chr17-35575265-T-C is described in ClinVar as [Benign]. Clinvar id is 322645.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX12	NM_000286.3	c.*517A>G		3_prime_UTR_variant	3/3	ENST00000225873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX12	ENST00000225873.9	c.*517A>G		3_prime_UTR_variant	3/3	1	NM_000286.3	P1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57195 AN: 151752 Hom.: 11589 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.380 AC: 2852 AN: 7514 Hom.: 607 Cov.: 0 AF XY: 0.370 AC XY: 1450 AN XY: 3922

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.289

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.377 AC: 57191 AN: 151868 Hom.: 11584 Cov.: 31 AF XY: 0.379 AC XY: 28100 AN XY: 74206

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.381

Alfa AF: 0.418 Hom.: 1746

Bravo AF: 0.364

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 3A (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	-0.85
Cadd	Benign	2.2
Dann	Benign	0.58

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: rs1046321; hg19: chr17-33902284;