6-136822702-CGGACGCCG-CGGACGCCGGGACGCCG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000288.4(PEX7):c.45_52dupGGGACGCC(p.His18ArgfsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000198 in 1,518,618 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. H18H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PEX7
NM_000288.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 6.05

Publications

0 publications found

Variant links:

Genes affected

PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

PEX7 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 9B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhizomelic chondrodysplasia punctata type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
adult Refsum disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 96 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-136822702-C-CGGACGCCG is Pathogenic according to our data. Variant chr6-136822702-C-CGGACGCCG is described in ClinVar as Pathogenic. ClinVar VariationId is 7784.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PEX7	NM_000288.4 link	c.45_52dupGGGACGCC	p.His18ArgfsTer35	frameshift_variant	Exon 1 of 10	ENST00000318471.5	NP_000279.1
PEX7	XM_006715502.3 link	c.45_52dupGGGACGCC	p.His18ArgfsTer35	frameshift_variant	Exon 1 of 7		XP_006715565.1
PEX7	XM_047418874.1 link	c.45_52dupGGGACGCC	p.His18ArgfsTer35	frameshift_variant	Exon 1 of 6		XP_047274830.1
PEX7	NM_001410945.1 link	c.-662_-661insGGACGCCG		upstream_gene_variant			NP_001397874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5 link	c.45_52dupGGGACGCC	p.His18ArgfsTer35	frameshift_variant	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151978

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1366640

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

674566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29016

American (AMR)

AF:

0.00

AC:

AN:

34508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24504

East Asian (EAS)

AF:

0.00

AC:

AN:

33796

South Asian (SAS)

AF:

0.00

AC:

AN:

78026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4146

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1072018

Other (OTH)

AF:

0.00

AC:

AN:

56870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.00000658

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2086

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 9B

Pathogenic:2

Oct 15, 2023

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.His18Argfs*35) in the PEX7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX7 are known to be pathogenic (PMID: 12325024, 12522768, 20301447). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with rhizomelic chondrodysplasia punctata (PMID: 11781871). ClinVar contains an entry for this variant (Variation ID: 7784). For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Rhizomelic chondrodysplasia punctata type 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.1

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over