chr17-35578449-A-G

Position:

• chr17-35578449-A-G

Variant summary

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

The ENST00000225873.9(PEX12):​c.-428T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 302,614 control chromosomes in the GnomAD database, including 103,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54408 hom., cov: 31)
  • Exomes 𝑓: 0.80 (48819 hom.)
• Consequence: PEX12 ENST00000225873.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.444

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=-0.88).
• BP6: Variant 17-35578449-A-G is Benign according to our data. Variant chr17-35578449-A-G is described in ClinVar as [Benign]. Clinvar id is 322663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX12	NM_000286.3	c.-428T>C		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.-428T>C		5_prime_UTR_variant	1/3	1	NM_000286.3	ENSP00000225873	P1
PEX12	ENST00000586663.2	c.-428T>C		5_prime_UTR_variant	1/3	1		ENSP00000466894
PEX12	ENST00000585380.1	c.-57+237T>C		intron_variant		4		ENSP00000466280
AP2B1	ENST00000589774.5	c.-24+328A>G		intron_variant		4		ENSP00000468183

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127876 AN: 152004 Hom.: 54343 Cov.: 31

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.779

Gnomad OTH AF: 0.828

GnomAD4 exome AF: 0.802 AC: 120683 AN: 150492 Hom.: 48819 Cov.: 0 AF XY: 0.805 AC XY: 65721 AN XY: 81626

Gnomad4 AFR exome AF: 0.959

Gnomad4 AMR exome AF: 0.892

Gnomad4 ASJ exome AF: 0.721

Gnomad4 EAS exome AF: 0.877

Gnomad4 SAS exome AF: 0.835

Gnomad4 FIN exome AF: 0.755

Gnomad4 NFE exome AF: 0.775

Gnomad4 OTH exome AF: 0.798

GnomAD4 genome AF: 0.841 AC: 128000 AN: 152122 Hom.: 54408 Cov.: 31 AF XY: 0.843 AC XY: 62636 AN XY: 74338

Gnomad4 AFR AF: 0.960

Gnomad4 AMR AF: 0.870

Gnomad4 ASJ AF: 0.728

Gnomad4 EAS AF: 0.887

Gnomad4 SAS AF: 0.855

Gnomad4 FIN AF: 0.750

Gnomad4 NFE AF: 0.779

Gnomad4 OTH AF: 0.829

Alfa AF: 0.792 Hom.: 60218

Bravo AF: 0.855

Asia WGS AF: 0.901 AC: 3130 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -

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	-0.88
CADD	Benign	4.2
DANN	Benign	0.53

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: rs321600; hg19: chr17-33905468;