6-136845652-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000288.4(PEX7):c.377A>C(p.Gln126Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00443 in 1,611,638 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 12 hom. )

Consequence

PEX7
NM_000288.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 5.55

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015132815).

BP6

Variant 6-136845652-A-C is Benign according to our data. Variant chr6-136845652-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00363 (553/152282) while in subpopulation NFE AF = 0.00512 (348/68022). AF 95% confidence interval is 0.00467. There are 2 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4 link	c.377A>C	p.Gln126Pro	missense_variant	Exon 4 of 10	ENST00000318471.5	NP_000279.1	O00628-1Q6FGN1
PEX7	NM_001410945.1 link	c.263A>C	p.Gln88Pro	missense_variant	Exon 4 of 10		NP_001397874.1
PEX7	XM_047418874.1 link	c.377A>C	p.Gln126Pro	missense_variant	Exon 4 of 6		XP_047274830.1
PEX7	XM_006715502.3 link	c.339+19183A>C		intron_variant	Intron 3 of 6		XP_006715565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5 link	c.377A>C	p.Gln126Pro	missense_variant	Exon 4 of 10	1	NM_000288.4	ENSP00000315680.3		O00628-1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

553

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00512

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00389

AC:

978

AN:

251428

AF XY:

0.00392

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00452

AC:

6589

AN:

1459356

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

3179

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33444

American (AMR)

AF:

0.00174

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00712

AC:

186

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000209

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.0113

AC:

601

AN:

53412

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00485

AC:

5387

AN:

1109740

Other (OTH)

AF:

0.00474

AC:

286

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

297

593

890

1186

1483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00363

AC:

553

AN:

152282

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41558

American (AMR)

AF:

0.00176

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0108

AC:

115

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00512

AC:

348

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00380

AC:

461

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jan 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PEX7: BS1, BS2 -

Jul 01, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jun 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2016

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 9B

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Rhizomelic chondrodysplasia punctata type 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhizomelic chondrodysplasia punctata

Benign:1

May 10, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Jan 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

.;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

0.062

MutationAssessor

Benign

0.25

N;N

PhyloP100

5.6

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.62

Sift

Benign

0.10

T;T

Sift4G

Benign

0.093

T;T

Polyphen

0.82

.;P

Vest4

0.77

MVP

1.0

MPC

0.51

ClinPred

0.029

GERP RS

5.9

Varity_R

0.46

gMVP

0.69

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over