rs63535662

Positions:

• chr6-136822702-CGGACGCCG-C
• chr6-136822702-CGGACGCCG-CGGACGCCGGGACGCCG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000288.4(PEX7):​c.45_52del​(p.Gly16ArgfsTer37) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R13R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PEX7 NM_000288.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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-CGGACGCCG-C is Pathogenic according to our data. Variant chr6-136822702-CGGACGCCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2136476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136822702-CGGACGCCG-C is described in Lovd as [Pathogenic]. Variant chr6-136822702-CGGACGCCG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX7	NM_000288.4	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant	1/10	ENST00000318471.5
PEX7	XM_006715502.3	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant	1/7
PEX7	XM_047418874.1	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000318471.5	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant	1/10	1	NM_000288.4	P1
PEX7	ENST00000367756.8	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant	1/4	3
PEX7	ENST00000541292.6	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant, NMD_transcript_variant	1/11	5
PEX7	ENST00000678593.1	c.45_52del	p.Gly16ArgfsTer37	frameshift_variant, NMD_transcript_variant	1/8

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 9B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 12, 2022	For these reasons, this variant has been classified as Pathogenic. This variant is also known as 45delGGGACGCC (P15fs). This premature translational stop signal has been observed in individual(s) with rhizomelic chondrodysplasia punctata (PMID: 12325024). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly16Argfs*37) 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63535662; hg19: chr6-137143840;