rs141238034

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000287.4(PEX6):c.2644G>A(p.Val882Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,614,138 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 43 hom., cov: 32)

Exomes 𝑓: 0.026 ( 598 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.61

Publications

10 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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000287.4

BP4

Computational evidence support a benign effect (MetaRNN=0.009148866).

BP6

Variant 6-42965097-C-T is Benign according to our data. Variant chr6-42965097-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3197/152310) while in subpopulation NFE AF = 0.0274 (1866/68030). AF 95% confidence interval is 0.0264. There are 43 homozygotes in GnomAd4. There are 1648 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.2644G>A	p.Val882Ile	missense_variant	Exon 15 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.2644G>A	p.Val882Ile	missense_variant	Exon 15 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.*180G>A		3_prime_UTR_variant	Exon 13 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3202

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00955

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.0233

Gnomad SAS

AF:

0.0254

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0226

AC:

5690

AN:

251470

AF XY:

0.0234

show subpopulations

Gnomad AFR exome

AF:

0.00861

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.0403

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0239

GnomAD4 exome

AF:

0.0265

AC:

38684

AN:

1461828

Hom.:

598

Cov.:

AF XY:

0.0264

AC XY:

19178

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00756

AC:

253

AN:

33480

American (AMR)

AF:

0.00736

AC:

329

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00627

AC:

164

AN:

26136

East Asian (EAS)

AF:

0.0163

AC:

649

AN:

39698

South Asian (SAS)

AF:

0.0251

AC:

2168

AN:

86254

European-Finnish (FIN)

AF:

0.0397

AC:

2121

AN:

53418

Middle Eastern (MID)

AF:

0.00867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0284

AC:

31533

AN:

1111956

Other (OTH)

AF:

0.0235

AC:

1417

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2220

4439

6659

8878

11098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1218

2436

3654

4872

6090

<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:

0.0210

AC:

3197

AN:

152310

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1648

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00950

AC:

395

AN:

41570

American (AMR)

AF:

0.00778

AC:

119

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.0231

AC:

120

AN:

5186

South Asian (SAS)

AF:

0.0250

AC:

121

AN:

4832

European-Finnish (FIN)

AF:

0.0444

AC:

471

AN:

10598

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1866

AN:

68030

Other (OTH)

AF:

0.0128

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

164

327

491

654

818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0243

Hom.:

127

Bravo

AF:

0.0179

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.0277

AC:

238

ExAC

AF:

0.0220

AC:

2665

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:1

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.0

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.073

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.51

MutationAssessor

Benign

-0.77

PhyloP100

1.6

PrimateAI

Benign

0.35

PROVEAN

Benign

0.11

REVEL

Benign

0.29

Sift

Benign

1.0

Sift4G

Benign

0.63

Polyphen

0.46

Vest4

0.060

MPC

0.12

ClinPred

0.0090

GERP RS

2.6

Varity_R

0.021

gMVP

0.33

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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