rs148591292

Positions:

• chr6-136898242-G-C

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.903+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000749 in 1,535,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: PEX7 NM_000288.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 7.59

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-136898242-G-C is Pathogenic according to our data. Variant chr6-136898242-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136898242-G-C is described in Lovd as [Pathogenic]. Variant chr6-136898242-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX7	NM_000288.4	c.903+1G>C		splice_donor_variant		ENST00000318471.5	NP_000279.1
PEX7	NM_001410945.1	c.789+1G>C		splice_donor_variant			NP_001397874.1
PEX7	XM_006715502.3	c.609+1G>C		splice_donor_variant			XP_006715565.1
PEX7	XM_047418874.1			downstream_gene_variant			XP_047274830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.903+1G>C		splice_donor_variant		1	NM_000288.4	ENSP00000315680	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152084 Hom.: 0 Cov.: 32

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251110 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000708 AC: 98 AN: 1383404 Hom.: 0 Cov.: 23 AF XY: 0.0000707 AC XY: 49 AN XY: 693132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000865

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 1 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2018	Variant summary: PEX7 c.903+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Braverman 2002). The variant allele was found at a frequency of 6.9e-05 in 276934 control chromosomes. c.903+1G>C has been reported in the literature in multiple individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (e.g. Motley 2002, Huffnagel 2013, Braverman 2002). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_000288.3(PEX7):c.903+1G>C(aka IVS9+1G>C) is classified as pathogenic in the context of type 1 rhizomelic chondrodysplasia punctata. Sources cited for classification include the following: PMID 9090383 and 12325024. Classification of NM_000288.3(PEX7):c.903+1G>C(aka IVS9+1G>C) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2024	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect on splicing with skipping of exon 9, leading to premature termination of the protein (PMID: 9090383); Also known as IVS9+1G>C; This variant is associated with the following publications: (PMID: 12325024, 25525159, 11781871, 23572185, 26408048, 31589614, 31980526, 31964843, 9090383) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 11, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with rhizomelic chondrodysplasia punctata (RCDP), this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing. Studies show this variant will result in premature termination of the protein (PMID: 9090383, 12325024). -

Peroxisome biogenesis disorder 9B Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change affects a donor splice site in intron 9 of the PEX7 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs148591292, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with rhizomelic chondrodysplasia punctata (PMID: 9090383, 11781871, 12325024, 23572185, 26408048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7785). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a new termination codon (PMID: 9090383). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

PEX7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The PEX7 c.903+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.903+1G>C variant has been reported in four studies in which it is found in at least 23 patients with rhizomelic chondrodysplasia punctate, including two in a homozygous state, 15 in a compound heterozygous state, and six individuals of unknown zygosity (Braverman et al. 2002; Motley et al. 2002; Huffnagel et al. 2013; Duker et al. 2016). The variant was absent from at least 100 control chromosomes and is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Northern blot analysis on PEX7 mRNA from an individual who was homozygous for the c.903+1G>C variant revealed a band that corresponded to a shorter transcript than in controls, which was the result of exon skipping (Braverman et al. 2002). Based on the collective evidence and the potential impact of splice donor variants, the c.903+1G>C variant is classified as pathogenic for PEX7-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Phytanic acid storage disease;C1859133:Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Rhizomelic chondrodysplasia punctata Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs148591292; hg19: chr6-137219380;