rs2274515

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000244546.4(PEX6):c.2117G>A(p.Cys706Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,612,834 control chromosomes in the GnomAD database, including 4,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 564 hom., cov: 32)

Exomes 𝑓: 0.062 ( 4085 hom. )

Consequence

PEX6
ENST00000244546.4 missense, splice_region

Scores

Splicing: ADA: 0.002506

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.32

Variant links:

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]

PEX6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014739037).

BP6

Variant 6-42965788-C-T is Benign according to our data. Variant chr6-42965788-C-T is described in ClinVar as [Benign]. Clinvar id is 92785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42965788-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4 linkuse as main transcript	c.2364G>A	p.Val788=	splice_region_variant, synonymous_variant	13/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000244546.4 linkuse as main transcript	c.2117G>A	p.Cys706Tyr	missense_variant, splice_region_variant	11/15	1			Q13608-2
PEX6	ENST00000304611.13 linkuse as main transcript	c.2364G>A	p.Val788=	splice_region_variant, synonymous_variant	13/17	1	NM_000287.4	P1	Q13608-1

Frequencies

GnomAD3 genomes

AF:

0.0660

AC:

10041

AN:

152066

Hom.:

559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0532

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.0455

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.0579

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0684

GnomAD3 exomes

AF:

0.0901

AC:

22604

AN:

250900

Hom.:

1650

AF XY:

0.0865

AC XY:

11744

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.0548

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.0450

Gnomad EAS exome

AF:

0.149

Gnomad SAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.0596

Gnomad NFE exome

AF:

0.0464

Gnomad OTH exome

AF:

0.0789

GnomAD4 exome

AF:

0.0617

AC:

90120

AN:

1460650

Hom.:

4085

Cov.:

AF XY:

0.0629

AC XY:

45724

AN XY:

726690

show subpopulations

Gnomad4 AFR exome

AF:

0.0552

Gnomad4 AMR exome

AF:

0.205

Gnomad4 ASJ exome

AF:

0.0494

Gnomad4 EAS exome

AF:

0.154

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.0584

Gnomad4 NFE exome

AF:

0.0476

Gnomad4 OTH exome

AF:

0.0703

GnomAD4 genome

AF:

0.0661

AC:

10052

AN:

152184

Hom.:

564

Cov.:

AF XY:

0.0696

AC XY:

5178

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0530

Gnomad4 AMR

AF:

0.151

Gnomad4 ASJ

AF:

0.0455

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.149

Gnomad4 FIN

AF:

0.0579

Gnomad4 NFE

AF:

0.0452

Gnomad4 OTH

AF:

0.0743

Alfa

AF:

0.0540

Hom.:

759

Bravo

AF:

0.0722

TwinsUK

AF:

0.0458

AC:

170

ALSPAC

AF:

0.0524

AC:

202

ESP6500AA

AF:

0.0567

AC:

250

ESP6500EA

AF:

0.0447

AC:

384

ExAC

AF:

0.0860

AC:

10436

Asia WGS

AF:

0.184

AC:

638

AN:

3478

EpiCase

AF:

0.0447

EpiControl

AF:

0.0444

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2018	Variant summary: Variant c.2364G>A (p.Val788Val) affects a non-conserved neucleotide resulting a synonymous change in the ATPase, AAA-type, core domain of the encoded protein. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.086 in 276948 control chromosomes in the gnomAD database, including 1712 homozygotes. The observed variant frequency is approximately 44.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX6 causing Zellweger Syndrome phenotype (0.0019), strongly suggesting that the variant is benign. c.2364G>A has been reported in the literature in individuals affected with Zellweger Syndrome and authors listed variant as SNP and neutral (Yik_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar and classified the variant as benign (2 labs)/likely benign (1 lab). Based on the evidence outlined above, the variant was classified as benign. -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Heimler syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Peroxisome biogenesis disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Peroxisome biogenesis disorder 4B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Pathogenic

0.21

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0015

MetaSVM

Uncertain

0.42

MutationTaster

Benign

0.94

P;P

PROVEAN

Benign

0.30

REVEL

Benign

0.29

Sift

Benign

0.11

Sift4G

Benign

0.16

Vest4

0.13

ClinPred

0.0080

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.094

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over