rs144942544

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000466.3(PEX1):c.1579A>G(p.Thr527Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,459,962 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T527T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 1.97

Publications

7 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:

ENSG00000244055 (HGNC:):

ENSG00000244055 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007453084).

BP6

Variant 7-92510952-T-C is Benign according to our data. Variant chr7-92510952-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 493456.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00218 (332/152358) while in subpopulation NFE AF = 0.00362 (246/68032). AF 95% confidence interval is 0.00324. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.1579A>G	p.Thr527Ala	missense_variant	Exon 8 of 24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 link	c.1579A>G	p.Thr527Ala	missense_variant	Exon 8 of 24	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

334

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00206

AC:

512

AN:

248932

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.000515

Gnomad AMR exome

AF:

0.000931

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000833

Gnomad NFE exome

AF:

0.00349

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00249

AC:

3260

AN:

1307604

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1643

AN XY:

658608

show subpopulations

African (AFR)

AF:

0.000393

AC:

AN:

30546

American (AMR)

AF:

0.00104

AC:

AN:

44392

Ashkenazi Jewish (ASJ)

AF:

0.000159

AC:

AN:

25166

East Asian (EAS)

AF:

0.00

AC:

AN:

38846

South Asian (SAS)

AF:

0.00166

AC:

137

AN:

82432

European-Finnish (FIN)

AF:

0.000657

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

5448

European-Non Finnish (NFE)

AF:

0.00294

AC:

2860

AN:

972418

Other (OTH)

AF:

0.00256

AC:

141

AN:

55088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

132

264

395

527

659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00218

AC:

332

AN:

152358

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41584

American (AMR)

AF:

0.00131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00124

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00362

AC:

246

AN:

68032

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00305

Hom.:

Bravo

AF:

0.00240

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000467

AC:

ESP6500EA

AF:

0.00342

AC:

ExAC

AF:

0.00201

AC:

244

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PEX1: BS2 -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

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

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PEX1 p.Thr527Ala variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs144942544), ClinVar (classified as likely benign by EGL Genetic Diagnostics and as a VUS by Mayo Clinic Genetic Testing Laboratories and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was also identified in control databases in 587 of 280334 chromosomes at a frequency of 0.002094 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 458 of 128286 chromosomes (freq: 0.00357), Other in 13 of 7140 chromosomes (freq: 0.001821), South Asian in 48 of 30138 chromosomes (freq: 0.001593), Latino in 32 of 35238 chromosomes (freq: 0.000908), European (Finnish) in 19 of 25088 chromosomes (freq: 0.000757) and African in 17 of 24248 chromosomes (freq: 0.000701); it was not observed in the Ashkenazi Jewish, and East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr527 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 1B

Uncertain:1Benign:1

Aug 21, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Uncertain:1Benign:1

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:2

Nov 15, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PEX1 c.1579A>G (p.Thr527Ala) results in a non-conservative amino acid change in 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 0.0021 in 248932 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.0021 vs 0.0039). However, this frequency is significantly higher than the frequency of the most common pathogenic variant in PEX1 (c.2097dupT/p.Ile700TyrfsTer42, 0.00048 in gnomAD), suggesting the variant of interest is unlikely to be pathogenic. c.1579A>G has been reported in the literature in individuals affected with Zellweger Syndrome and retinal dystrophy without specified allele in trans (Ebberink_2010, Watson_2014). These reports do not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (1x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as likely benign. -

Zellweger spectrum disorders

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 10, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PEX1-related disorder

Benign:1

Feb 11, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Heimler syndrome 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

0.079

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.051

.;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.79

T;T;T

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.4

.;M;.

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.71

T;T;T

Polyphen

0.17

.;B;.

Vest4

0.17

MVP

0.78

MPC

0.18

ClinPred

0.017

GERP RS

0.89

Varity_R

0.045

gMVP

0.37

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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