6-42964462-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000287.4(PEX6):c.2816C>A(p.Pro939Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,612,380 control chromosomes in the GnomAD database, including 152,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P939E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 12620 hom., cov: 33)

Exomes 𝑓: 0.43 ( 139514 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.306

Publications

64 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.4440885E-4).

BP6

Variant 6-42964462-G-T is Benign according to our data. Variant chr6-42964462-G-T is described in ClinVar as Benign. ClinVar VariationId is 92787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.2816C>A	p.Pro939Gln	missense_variant	Exon 17 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 link	c.2816C>A	p.Pro939Gln	missense_variant	Exon 17 of 17	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4 link	c.*352C>A		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000244546.4

Frequencies

GnomAD3 genomes

AF:

0.402

AC:

61022

AN:

151838

Hom.:

12616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.583

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.403

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.453

Gnomad OTH

AF:

0.414

GnomAD2 exomes

AF:

0.383

AC:

95103

AN:

248532

AF XY:

0.394

show subpopulations

Gnomad AFR exome

AF:

0.378

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.414

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.449

Gnomad OTH exome

AF:

0.413

GnomAD4 exome

AF:

0.432

AC:

630242

AN:

1460424

Hom.:

139514

Cov.:

AF XY:

0.433

AC XY:

314748

AN XY:

726538

show subpopulations

African (AFR)

AF:

0.377

AC:

12629

AN:

33462

American (AMR)

AF:

0.273

AC:

12191

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

10788

AN:

26134

East Asian (EAS)

AF:

0.125

AC:

4952

AN:

39696

South Asian (SAS)

AF:

0.432

AC:

37279

AN:

86208

European-Finnish (FIN)

AF:

0.394

AC:

20938

AN:

53110

Middle Eastern (MID)

AF:

0.465

AC:

2543

AN:

5474

European-Non Finnish (NFE)

AF:

0.453

AC:

503781

AN:

1111304

Other (OTH)

AF:

0.417

AC:

25141

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

19055

38110

57166

76221

95276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14878

29756

44634

59512

74390

<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:

0.402

AC:

61059

AN:

151956

Hom.:

12620

Cov.:

AF XY:

0.398

AC XY:

29523

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.374

AC:

15496

AN:

41480

American (AMR)

AF:

0.339

AC:

5182

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

1415

AN:

3472

East Asian (EAS)

AF:

0.104

AC:

537

AN:

5178

South Asian (SAS)

AF:

0.403

AC:

1937

AN:

4806

European-Finnish (FIN)

AF:

0.403

AC:

4244

AN:

10532

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.453

AC:

30728

AN:

67886

Other (OTH)

AF:

0.412

AC:

870

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1881

3762

5643

7524

9405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.432

Hom.:

70208

Bravo

AF:

0.394

TwinsUK

AF:

0.456

AC:

1689

ALSPAC

AF:

0.463

AC:

1784

ESP6500AA

AF:

0.390

AC:

1720

ESP6500EA

AF:

0.446

AC:

3832

ExAC

AF:

0.390

AC:

47300

Asia WGS

AF:

0.257

AC:

895

AN:

3478

EpiCase

AF:

0.457

EpiControl

AF:

0.458

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 10, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PEX6 c.2816C>A (p.Pro939Gln) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 46985/120122 control chromosomes (9823 homozygotes) at a frequency of 0.391144, which is approximately 202 times the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365), evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:2

Jan 13, 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.

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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

Zellweger spectrum disorders

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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

Benign

0.088

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

6.6

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.059

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.82

MetaRNN

Benign

0.00024

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.5

PhyloP100

0.31

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.23

Sift

Benign

0.15

Sift4G

Benign

0.46

Vest4

0.074

ClinPred

0.0069

GERP RS

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.033

gMVP

0.12

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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