rs12386703

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000466.3(PEX1):c.-53C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 1,510,668 control chromosomes in the GnomAD database, including 4,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 483 hom., cov: 32)

Exomes 𝑓: 0.079 ( 4500 hom. )

Consequence

PEX1
NM_000466.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.442

Publications

12 publications found

Variant links:

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 1A (Zellweger)
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, Ambry Genetics
Heimler syndrome 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics
peroxisome biogenesis disorder 1B
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX1 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 (BayesDel_noAF=-0.78).

BP6

Variant 7-92528488-G-C is Benign according to our data. Variant chr7-92528488-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.-53C>G	5_prime_UTR_variant	Exon 1 of 24	ENST00000248633.9	NP_000457.1	O43933-1
PEX1	NM_001282677.2 link	c.-53C>G	5_prime_UTR_variant	Exon 1 of 23		NP_001269606.1	O43933A0A0C4DG33
PEX1	NM_001282678.2 link	c.-712C>G	5_prime_UTR_variant	Exon 1 of 24		NP_001269607.1	O43933B4DER6
PEX1	XM_047420472.1 link	c.-53C>G	5_prime_UTR_variant	Exon 1 of 23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PEX1	ENST00000248633.9 link	c.-53C>G	5_prime_UTR_variant	Exon 1 of 24	1	NM_000466.3	ENSP00000248633.4	O43933-1
PEX1	ENST00000428214.5 link	c.-53C>G	upstream_gene_variant		1		ENSP00000394413.1	A0A0C4DG33
PEX1	ENST00000438045.5 link	c.-53C>G	upstream_gene_variant		2		ENSP00000410438.1	O43933-2
PEX1	ENST00000484913.5 link	n.-49C>G	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0769

AC:

11705

AN:

152136

Hom.:

485

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0676

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0566

Gnomad ASJ

AF:

0.0894

Gnomad EAS

AF:

0.0309

Gnomad SAS

AF:

0.0623

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0876

Gnomad OTH

AF:

0.0828

GnomAD4 exome

AF:

0.0791

AC:

107427

AN:

1358414

Hom.:

4500

Cov.:

AF XY:

0.0786

AC XY:

52369

AN XY:

665874

show subpopulations

African (AFR)

AF:

0.0691

AC:

2122

AN:

30728

American (AMR)

AF:

0.0609

AC:

2046

AN:

33574

Ashkenazi Jewish (ASJ)

AF:

0.0855

AC:

1964

AN:

22972

East Asian (EAS)

AF:

0.0362

AC:

1283

AN:

35442

South Asian (SAS)

AF:

0.0715

AC:

5378

AN:

75220

European-Finnish (FIN)

AF:

0.104

AC:

3986

AN:

38266

Middle Eastern (MID)

AF:

0.0516

AC:

216

AN:

4182

European-Non Finnish (NFE)

AF:

0.0811

AC:

86069

AN:

1061700

Other (OTH)

AF:

0.0775

AC:

4363

AN:

56330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5729

11458

17187

22916

28645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3222

6444

9666

12888

16110

<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:

0.0769

AC:

11705

AN:

152254

Hom.:

483

Cov.:

AF XY:

0.0769

AC XY:

5724

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0676

AC:

2809

AN:

41566

American (AMR)

AF:

0.0563

AC:

861

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0894

AC:

310

AN:

3468

East Asian (EAS)

AF:

0.0309

AC:

160

AN:

5172

South Asian (SAS)

AF:

0.0621

AC:

300

AN:

4828

European-Finnish (FIN)

AF:

0.100

AC:

1060

AN:

10596

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0876

AC:

5957

AN:

68010

Other (OTH)

AF:

0.0819

AC:

173

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

571

1142

1712

2283

2854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0891

Hom.:

Bravo

AF:

0.0724

Asia WGS

AF:

0.0540

AC:

187

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 19, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Zellweger spectrum disorders

Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16088892) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.7

(source)

DANN

Benign

0.57

PhyloP100

-0.44

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism (auto)

(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