NM_000287.4:c.530delC

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.530delC(p.Pro177HisfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,597,382 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P177P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PEX6
NM_000287.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.824

Publications

0 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 6-42978620-TG-T is Pathogenic according to our data. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978620-TG-T is described in CliVar as Pathogenic. Clinvar id is 2734863.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.530delC	p.Pro177HisfsTer29	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.530delC	p.Pro177HisfsTer29	frameshift_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.530delC	p.Pro177HisfsTer29	frameshift_variant	Exon 1 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151678

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:

0.000379

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

216074

AF XY:

0.0000418

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:

0.000405

Gnomad NFE exome

AF:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1445704

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

718846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.00

AC:

AN:

42882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39046

South Asian (SAS)

AF:

0.00

AC:

AN:

85128

European-Finnish (FIN)

AF:

0.000413

AC:

AN:

46058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107832

Other (OTH)

AF:

0.0000167

AC:

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.0000396

AC:

AN:

151678

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41230

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000198

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heimler syndrome 2

Pathogenic:1

Jan 12, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder

Pathogenic:1

Jan 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 10408779). This sequence change creates a premature translational stop signal (p.Pro177Hisfs*29) 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: 8670792, 19877282, 21031596). This variant is present in population databases (rs61753213, gnomAD 0.07%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.82

Mutation Taster

=1/199

disease causing (fs/PTC)

(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