6-143490561-A-G

Position:

• chr6-143490561-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6_Moderate BS1

The ENST00000367591.5(PEX3):​c.*1335A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000328 in 560,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: PEX3 ENST00000367591.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.09

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]

VDAC1P8 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 6-143490561-A-G is Benign according to our data. Variant chr6-143490561-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 355594.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000473 (72/152324) while in subpopulation EAS AF= 0.0131 (68/5182). AF 95% confidence interval is 0.0106. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX3	NM_003630.3	c.*1335A>G		3_prime_UTR_variant	12/12	ENST00000367591.5	NP_003621.1
VDAC1P8		n.143490561A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX3	ENST00000367591.5	c.*1335A>G		3_prime_UTR_variant	12/12	1	NM_003630.3	ENSP00000356563.4
VDAC1P8	ENST00000406025.2	n.47A>G		non_coding_transcript_exon_variant	1/1	6
VDAC1P8	ENST00000610068.5	n.138A>G		non_coding_transcript_exon_variant	1/5	5
ENSG00000278206	ENST00000591892.2	n.270+5313A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000274 AC: 112 AN: 408526 Hom.: 1 Cov.: 7 AF XY: 0.000256 AC XY: 55 AN XY: 214602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000703

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00873

Gnomad4 SAS exome AF: 0.000100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000104

Gnomad4 OTH exome AF: 0.000389

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000827

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 10A (Zellweger) Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9403495; hg19: chr6-143811698;