chr6-42965726-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000287.4(PEX6):c.2426C>T(p.Ala809Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,613,654 control chromosomes in the GnomAD database, including 3,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 503 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2542 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 10.0

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 4A (Zellweger)
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
peroxisome biogenesis disorder 4B
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Heimler syndrome 2
Inheritance: AR Classification: MODERATE Submitted by: G2P
autosomal recessive cerebellar ataxia-blindness-deafness syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000287.4

BP4

Computational evidence support a benign effect (MetaRNN=0.004077047).

BP6

Variant 6-42965726-G-A is Benign according to our data. Variant chr6-42965726-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.2426C>T	p.Ala809Val	missense_variant	Exon 13 of 17	ENST00000304611.13	NP_000278.3	Q13608-1A0A024RD09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 link	c.2426C>T	p.Ala809Val	missense_variant	Exon 13 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.2179C>T	p.Pro727Ser	missense_variant	Exon 11 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0718

AC:

10919

AN:

152008

Hom.:

503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0554

Gnomad SAS

AF:

0.0598

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0533

Gnomad OTH

AF:

0.0655

GnomAD2 exomes

AF:

0.0553

AC:

13904

AN:

251470

AF XY:

0.0546

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.0332

Gnomad ASJ exome

AF:

0.0450

Gnomad EAS exome

AF:

0.0670

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0536

Gnomad OTH exome

AF:

0.0536

GnomAD4 exome

AF:

0.0558

AC:

81539

AN:

1461528

Hom.:

2542

Cov.:

AF XY:

0.0557

AC XY:

40500

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.131

AC:

4387

AN:

33456

American (AMR)

AF:

0.0346

AC:

1547

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

1159

AN:

26130

East Asian (EAS)

AF:

0.0639

AC:

2535

AN:

39696

South Asian (SAS)

AF:

0.0611

AC:

5266

AN:

86254

European-Finnish (FIN)

AF:

0.0350

AC:

1872

AN:

53414

Middle Eastern (MID)

AF:

0.0792

AC:

457

AN:

5768

European-Non Finnish (NFE)

AF:

0.0547

AC:

60763

AN:

1111702

Other (OTH)

AF:

0.0588

AC:

3553

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

4322

8645

12967

17290

21612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2342

4684

7026

9368

11710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0718

AC:

10928

AN:

152126

Hom.:

503

Cov.:

AF XY:

0.0692

AC XY:

5150

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.130

AC:

5394

AN:

41458

American (AMR)

AF:

0.0406

AC:

621

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3470

East Asian (EAS)

AF:

0.0553

AC:

286

AN:

5170

South Asian (SAS)

AF:

0.0590

AC:

284

AN:

4816

European-Finnish (FIN)

AF:

0.0344

AC:

365

AN:

10602

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0533

AC:

3627

AN:

67996

Other (OTH)

AF:

0.0653

AC:

138

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

492

985

1477

1970

2462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0595

Hom.:

1070

Bravo

AF:

0.0758

TwinsUK

AF:

0.0510

AC:

189

ALSPAC

AF:

0.0545

AC:

210

ESP6500AA

AF:

0.133

AC:

585

ESP6500EA

AF:

0.0535

AC:

460

ExAC

AF:

0.0582

AC:

7069

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

EpiCase

AF:

0.0550

EpiControl

AF:

0.0530

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11873320, 20981092, 19142205, 27884173, 30245029) -

Nov 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:3

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Zellweger spectrum disorders

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Heimler syndrome 2

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 4B

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0041

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

0.34

PhyloP100

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.86

MPC

0.63

ClinPred

0.040

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.81

Mutation Taster

=8/92

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over