6-143450846-T-C

Variant summary

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

The NM_003630.3(PEX3):c.-197T>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 0.0133 in 756,068 control chromosomes in the GnomAD database, including 611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (102 hom., cov: 32)
  • Exomes 𝑓: 0.013 (509 hom.)
• Consequence: PEX3 NM_003630.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.708

Genes affected

PEX3 (HGNC:8858): (peroxisomal biogenesis factor 3) The product of this gene is involved in peroxisome biosynthesis and integrity. It assembles membrane vesicles before the matrix proteins are translocated. 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 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 6-143450846-T-C is Benign according to our data. Variant chr6-143450846-T-C is described in ClinVar as [Benign]. Clinvar id is 355569.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX3	NM_003630.3	c.-197T>C		5_prime_UTR_variant	1/12	ENST00000367591.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX3	ENST00000367591.5	c.-197T>C		5_prime_UTR_variant	1/12	1	NM_003630.3	P1
PEX3	ENST00000367592.5	c.-197T>C		5_prime_UTR_variant	1/7	5

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152206 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0959

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0135 AC: 8135 AN: 603744 Hom.: 509 Cov.: 8 AF XY: 0.0134 AC XY: 4332 AN XY: 322430

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00373

Gnomad4 SAS exome AF: 0.0404

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.000841

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0126 AC: 1920 AN: 152324 Hom.: 102 Cov.: 32 AF XY: 0.0143 AC XY: 1069 AN XY: 74496

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0966

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00676

Gnomad4 SAS AF: 0.0426

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.0204

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 10A (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	13
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs184934783; hg19: chr6-143771983;