6-42978941-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000287.4(PEX6):c.210G>A(p.Gly70Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,494,934 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., cov: 33)

Exomes 𝑓: 0.012 ( 120 hom. )

Consequence

PEX6
NM_000287.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.167

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 6-42978941-C-T is Benign according to our data. Variant chr6-42978941-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.167 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00645 (981/152204) while in subpopulation NFE AF = 0.0118 (805/67980). AF 95% confidence interval is 0.0112. There are 4 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.210G>A	p.Gly70Gly	synonymous_variant	Exon 1 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.210G>A	p.Gly70Gly	synonymous_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.210G>A	p.Gly70Gly	synonymous_variant	Exon 1 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.00645

AC:

981

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00615

AC:

575

AN:

93436

AF XY:

0.00593

show subpopulations

Gnomad AFR exome

AF:

0.00482

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00326

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00492

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.00498

GnomAD4 exome

AF:

0.0120

AC:

16096

AN:

1342730

Hom.:

120

Cov.:

AF XY:

0.0116

AC XY:

7652

AN XY:

662302

show subpopulations

African (AFR)

AF:

0.00232

AC:

AN:

27190

American (AMR)

AF:

0.00279

AC:

AN:

30054

Ashkenazi Jewish (ASJ)

AF:

0.00389

AC:

AN:

23670

East Asian (EAS)

AF:

0.0000323

AC:

AN:

30948

South Asian (SAS)

AF:

0.000709

AC:

AN:

74702

European-Finnish (FIN)

AF:

0.00518

AC:

174

AN:

33622

Middle Eastern (MID)

AF:

0.00152

AC:

AN:

3948

European-Non Finnish (NFE)

AF:

0.0142

AC:

15050

AN:

1062772

Other (OTH)

AF:

0.0103

AC:

573

AN:

55824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

879

1758

2637

3516

4395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.00645

AC:

981

AN:

152204

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

435

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41548

American (AMR)

AF:

0.00216

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00368

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0118

AC:

805

AN:

67980

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00836

Hom.:

Bravo

AF:

0.00647

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PEX6: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jun 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PEX6 c.210G>A alters a non-conserved nucleotide resulting in a synonymous change. 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 0.0064 in 122756 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 3.28 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. The variant, c.210G>A, has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Yik_2009) but were classified as neutral. These report(s) do not provide unequivocal conclusions about association of the variant with Zellweger Syndrome . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

PEX6-related disorder

Benign:1

Nov 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2

Benign:1

Aug 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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 03, 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

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

-0.17

PromoterAI

-0.035

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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