rs121909151

Positions:

chr6-136869909-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000288.4(PEX7):c.653C>T(p.Ala218Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,613,612 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

PEX7
NM_000288.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 6.09

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 16 ACMG points.

PM1

In a repeat WD 4 (size 31) in uniprot entity PEX7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000288.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 6-136869909-C-T is Pathogenic according to our data. Variant chr6-136869909-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136869909-C-T is described in Lovd as [Pathogenic]. Variant chr6-136869909-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PEX7	NM_000288.4 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	7/10	ENST00000318471.5	NP_000279.1
PEX7	NM_001410945.1 linkuse as main transcript	c.539C>T	p.Ala180Val	missense_variant	7/10		NP_001397874.1
PEX7	XM_006715502.3 linkuse as main transcript	c.359C>T	p.Ala120Val	missense_variant	4/7		XP_006715565.1
PEX7	XM_047418874.1 linkuse as main transcript	c.526+23728C>T		intron_variant			XP_047274830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	7/10	1	NM_000288.4	ENSP00000315680	P1	O00628-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251372

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135852

show subpopulations

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:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461488

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000603

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000479

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 1

Pathogenic:4Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000288.3(PEX7):c.653C>T(A218V) is classified as likely pathogenic in the context of rhizomelic chondrodysplasia punctata type 1. Sources cited for classification include the following: PMID 12325024, 9090382, 9090381 and 11756410. Classification of NM_000288.3(PEX7):c.653C>T(A218V) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1997	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2020	Variant summary: PEX7 c.653C>T (p.Ala218Val) results in a non-conservative amino acid change located in the WD40-repeat-containing domain (IPR017986) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251372 control chromosomes. c.653C>T has been reported in the literature in multiple individuals affected with Rhizomelic Chondrodysplasia Punctata Type (example, Braverman_1997, Shimozawa_1999, Braverman_2002, Motley_2002). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired transport of PTS2 (peroxisome-targeting signal type 2 (PTS2) nonapeptide sequence) signal containing proteins into the peroxisomes (Braverman_1997, Mukai_2002). Three 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2024	Published functional studies demonstrate that the variant severely impairs protein function (PMID: 9090381); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9090381, 11756410, 10083738, 12325024, 31589614, 33337545, 11781871) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Aug 26, 2016	- -

Peroxisome biogenesis disorder 9B

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 218 of the PEX7 protein (p.Ala218Val). This variant is present in population databases (rs121909151, gnomAD 0.006%). This missense change has been observed in individuals with rhizomelic chondrodysplasia punctata (PMID: 9090381, 10083738, 11781871, 12325024). ClinVar contains an entry for this variant (Variation ID: 7781). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects PEX7 function (PMID: 11756410, 11781871). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1997	- -

PEX7-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2024

The PEX7 c.653C>T variant is predicted to result in the amino acid substitution p.Ala218Val. This variant has been reported to be the second most common pathogenic PEX7 variant and accounts for ~6-12% of the RCDP cases (Braverman et al. 1997. PubMed ID: 9090381; Motley et al. 2002. PubMed ID: 11781871).This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 22, 2021

- -

Rhizomelic chondrodysplasia punctata

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.84

L;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.086

T;T

Polyphen

0.23

.;B

Vest4

0.97

MutPred

0.93

Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);

MVP

0.85

MPC

0.16

ClinPred

0.48

GERP RS

5.8

Varity_R

0.18

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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