17-35578555-G-A

Position:

• chr17-35578555-G-A

Variant summary

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

The NM_000286.3(PEX12):​c.-534C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 214,666 control chromosomes in the GnomAD database, including 494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (374 hom., cov: 33)
  • Exomes 𝑓: 0.042 (120 hom.)
• Consequence: PEX12 NM_000286.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.863

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]

AP2B1 (HGNC:563): (adaptor related protein complex 2 subunit beta 1) The protein encoded by this gene is one of two large chain components of the assembly protein complex 2, which serves to link clathrin to receptors in coated vesicles. The encoded protein is found on the cytoplasmic face of coated vesicles in the plasma membrane. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-35578555-G-A is Benign according to our data. Variant chr17-35578555-G-A is described in ClinVar as [Benign]. Clinvar id is 322666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX12	NM_000286.3	c.-534C>T		5_prime_UTR_variant	1/3	ENST00000225873.9	NP_000277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX12	ENST00000225873.9	c.-534C>T		5_prime_UTR_variant	1/3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000585380.1	c.-57+131C>T		intron_variant		4		ENSP00000466280.1
AP2B1	ENST00000589774.5	c.-24+434G>A		intron_variant		4		ENSP00000468183.1
PEX12	ENST00000586663.2	n.-534C>T		upstream_gene_variant		1		ENSP00000466894.2

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8357 AN: 152126 Hom.: 371 Cov.: 33

Gnomad AFR AF: 0.0838

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0614

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0550

GnomAD4 exome AF: 0.0424 AC: 2646 AN: 62420 Hom.: 120 Cov.: 0 AF XY: 0.0435 AC XY: 1437 AN XY: 33020

Gnomad4 AFR exome AF: 0.0814

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.0464

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0550 AC: 8377 AN: 152246 Hom.: 374 Cov.: 33 AF XY: 0.0566 AC XY: 4217 AN XY: 74462

Gnomad4 AFR AF: 0.0838

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.0613

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0348 Hom.: 156

Bravo AF: 0.0646

Asia WGS AF: 0.127 AC: 441 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	Nov 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.69
CADD	Benign	11
DANN	Benign	0.91

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: rs2278950; hg19: chr17-33905574;