6-42964016-G-A

Variant summary

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

The NM_000287.4(PEX6):c.*319C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0691 in 558,780 control chromosomes in the GnomAD database, including 2,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (562 hom., cov: 31)
  • Exomes 𝑓: 0.070 (1492 hom.)
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.315

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-42964016-G-A is Benign according to our data. Variant chr6-42964016-G-A is described in ClinVar as [Benign]. Clinvar id is 356789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.*319C>T		3_prime_UTR_variant	17/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.*319C>T		3_prime_UTR_variant	17/17	1	NM_000287.4	P1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 9975 AN: 151404 Hom.: 557 Cov.: 31

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0687

GnomAD4 exome AF: 0.0702 AC: 28599 AN: 407256 Hom.: 1492 Cov.: 3 AF XY: 0.0730 AC XY: 15736 AN XY: 215646

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.0492

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0568

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0746

GnomAD4 genome AF: 0.0659 AC: 9986 AN: 151524 Hom.: 562 Cov.: 31 AF XY: 0.0693 AC XY: 5127 AN XY: 73982

Gnomad4 AFR AF: 0.0529

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0456

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0746

Alfa AF: 0.0623 Hom.: 220

Bravo AF: 0.0722

Asia WGS AF: 0.184 AC: 638 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 4A (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. -

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	-0.75
Cadd	Benign	9.2
Dann	Benign	0.56

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: rs736158; hg19: chr6-42931754;