rs61753209

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000287.4(PEX6):c.311delG(p.Gly104ValfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000409 in 1,516,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

PEX6
NM_000287.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.74

Publications

1 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-42978839-AC-A is Pathogenic according to our data. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978839-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 499109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.311delG	p.Gly104ValfsTer22	frameshift_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.311delG	p.Gly104ValfsTer22	frameshift_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.311delG	p.Gly104ValfsTer22	frameshift_variant	Exon 1 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

112424

AF XY:

0.0000160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000471

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000432

AC:

AN:

1364942

Hom.:

Cov.:

AF XY:

0.0000342

AC XY:

AN XY:

673454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28906

American (AMR)

AF:

0.00

AC:

AN:

33542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24504

East Asian (EAS)

AF:

0.00

AC:

AN:

33418

South Asian (SAS)

AF:

0.00

AC:

AN:

77532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4026

European-Non Finnish (NFE)

AF:

0.0000541

AC:

AN:

1072430

Other (OTH)

AF:

0.0000176

AC:

AN:

56880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67918

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000214

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 19, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31964843, 19877282) -

Peroxisome biogenesis disorder

Pathogenic:2

Jan 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gly104Valfs*22) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is present in population databases (rs61753209, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with PEX6-related disorders (PMID: 19877282). ClinVar contains an entry for this variant (Variation ID: 499109). For these reasons, this variant has been classified as Pathogenic. -

Oct 18, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PEX6 c.311delG (p.Gly104ValfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.8e-05 in 112824 control chromosomes (gnomAD and publication data). c.311delG has been reported in the literature in at least one compound heterozygous individual affected with Zellweger Syndrome (Ebberink_2010). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

PEX6-related disorder

Pathogenic:1

Jan 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PEX6 c.311delG variant is predicted to result in a frameshift and premature protein termination (p.Gly104Valfs*22). This variant has been reported in an individual with Zellweger syndrome (Table 2, Ebberink et al. 2010. PubMed ID: 19877282). This variant is reported in 0.0052% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in PEX6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B

Pathogenic:1

Sep 06, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Heimler syndrome 2

Pathogenic:1

Feb 01, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Zellweger spectrum disorders

Pathogenic:1

Feb 01, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.7

Mutation Taster

=4/196

disease causing (ClinVar)

(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