6-136822785-C-G

Position:

chr6-136822785-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000288.4(PEX7):c.120C>G(p.Tyr40Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000097 in 1,349,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y40Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PEX7
NM_000288.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 6-136822785-C-G is Pathogenic according to our data. Variant chr6-136822785-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136822785-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PEX7	NM_000288.4 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained	1/10	ENST00000318471.5
PEX7	XM_006715502.3 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained	1/7
PEX7	XM_047418874.1 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000318471.5 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained	1/10	1	NM_000288.4	P1	O00628-1
PEX7	ENST00000367756.8 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained	1/4	3
PEX7	ENST00000541292.6 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained, NMD_transcript_variant	1/11	5			O00628-2
PEX7	ENST00000678593.1 linkuse as main transcript	c.120C>G	p.Tyr40Ter	stop_gained, NMD_transcript_variant	1/8

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000833

AC:

AN:

24010

Hom.:

AF XY:

0.0000655

AC XY:

AN XY:

15258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000397

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:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

122

AN:

1198062

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

583098

show subpopulations

Gnomad4 AFR exome

AF:

0.0000833

Gnomad4 AMR exome

AF:

0.000248

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:

0.000116

Gnomad4 OTH exome

AF:

0.0000410

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2017	Variant summary: The PEX7 c.120C>G (p.Tyr40X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX7 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 5288 control chromosomes (indicated to be a low-quality site in ExAC). Multiple publications have cited the variant in affected individuals dx with RCDP1, however, it has been noted to also be found in Refsum Disease pts (van der Brink_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -

Peroxisome biogenesis disorder 9B

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change creates a premature translational stop signal (p.Tyr40*) 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 present in population databases (rs61753238, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with rhizomelic chondrodysplasia punctata type 1 and Refsum disease (PMID: 11781871, 12325024, 12522768). ClinVar contains an entry for this variant (Variation ID: 7788). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 10, 2024	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2021

The c.120C>G (p.Y40*) alteration, located in exon 1 (coding exon 1) of the PEX7 gene, consists of a C to G substitution at nucleotide position 120. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 40. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the G allele has an overall frequency of 0.01% (5/55,154) total alleles studied. The highest observed frequency was 0.06% (2/3,332) of Latino alleles. This alteration has been reported compound heterozygous with a second alteration in PEX7 in multiple patients with rhizomelic chondrodysplasia punctata (RCDP) or Refsum disease (Braverman, 2002; van den Brink, 2003). Motley et al. (2002) also reported this alteration in patients with RCDP. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 03, 2022

- -

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

Oct 31, 2018

- -

PEX7-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The PEX7 c.120C>G (p.Tyr40Ter) variant is a stop-gained variant that has been reported in five individuals, including two compound heterozygotes diagnosed with Refsum disease, one compound heterozygote diagnosed with rhizomelic chondrodysplasia punctate (RCDP), and two heterozygotes diagnosed with RCDP in whom a second variant was not identified (Motley et al. 2002; van den Brink et al. 2003; Wood et al. 2014). Control data are unavailable for this variant, which it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. In cultured skin fibroblasts from patients carrying the p.Tyr40Ter variant, van den Brink (2003) demonstrated that the variant leads to deficiency of phytanic acid alpha-oxidation, PhyH activity, and plasmalogen synthesis, defective subcellular localization, and an inability to restore thiolase protein transport, as compared to controls. Based on the evidence and the potential impact of stop-gained variants, the p.Tyr40Ter 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. -

Rhizomelic chondrodysplasia punctata

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

A;A;A

Vest4

0.79

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over