17-35575616-G-T

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.*166C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 724,962 control chromosomes in the GnomAD database, including 15,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3374 hom., cov: 32)
  • Exomes 𝑓: 0.20 (11948 hom.)
• Consequence: PEX12 NM_000286.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.396

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-35575616-G-T is Benign according to our data. Variant chr17-35575616-G-T is described in ClinVar as [Benign]. Clinvar id is 322651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX12	NM_000286.3	c.*166C>A		3_prime_UTR_variant	3/3	ENST00000225873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX12	ENST00000225873.9	c.*166C>A		3_prime_UTR_variant	3/3	1	NM_000286.3	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31444 AN: 151920 Hom.: 3368 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.198 AC: 113329 AN: 572924 Hom.: 11948 Cov.: 7 AF XY: 0.198 AC XY: 60371 AN XY: 305284

Gnomad4 AFR exome AF: 0.243

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.207 AC: 31477 AN: 152038 Hom.: 3374 Cov.: 32 AF XY: 0.209 AC XY: 15502 AN XY: 74326

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.221

Alfa AF: 0.187 Hom.: 4584

Bravo AF: 0.216

Asia WGS AF: 0.275 AC: 960 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.4
Dann	Benign	0.73

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: rs1037590; hg19: chr17-33902635; COSMIC: COSV56778063; COSMIC: COSV56778063;