rs200752969

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000466.3(PEX1):c.627G>A(p.Met209Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,548,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10B:2

Conservation

PhyloP100: -0.197

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013981968).

BP6

Variant 7-92517888-C-T is Benign according to our data. Variant chr7-92517888-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167445.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000112 (156/1395800) while in subpopulation MID AF = 0.0037 (20/5412). AF 95% confidence interval is 0.00245. There are 0 homozygotes in GnomAdExome4. There are 78 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.627G>A	p.Met209Ile	missense_variant	Exon 5 of 24	ENST00000248633.9	NP_000457.1	O43933-1
PEX1	NM_001282678.2 link	c.3G>A	p.Met1?	start_lost	Exon 5 of 24		NP_001269607.1	O43933B4DER6
PEX1	NM_001282677.2 link	c.627G>A	p.Met209Ile	missense_variant	Exon 5 of 23		NP_001269606.1	O43933A0A0C4DG33
PEX1	XM_047420472.1 link	c.627G>A	p.Met209Ile	missense_variant	Exon 5 of 23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 link	c.627G>A	p.Met209Ile	missense_variant	Exon 5 of 24	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000209

AC:

AN:

196000

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000481

Gnomad ASJ exome

AF:

0.00191

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

156

AN:

1395800

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

689056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30756

American (AMR)

AF:

0.000475

AC:

AN:

31596

Ashkenazi Jewish (ASJ)

AF:

0.000924

AC:

AN:

21646

East Asian (EAS)

AF:

0.00

AC:

AN:

39258

South Asian (SAS)

AF:

0.0000955

AC:

AN:

73320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50780

Middle Eastern (MID)

AF:

0.00370

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

0.0000783

AC:

AN:

1085634

Other (OTH)

AF:

0.000157

AC:

AN:

57398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000144

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.000202

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Peroxisome biogenesis disorder 1A (Zellweger)

Pathogenic:1Uncertain:2

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Likely pathogenic

Review Status:no assertion criteria provided

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. -

May 15, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified

Uncertain:1Benign:1

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PEX1 c.627G>A (p.Met209Ile) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.00021 in 196000 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.00021 vs 0.0039), allowing no conclusion about variant significance. c.627G>A has been reported in the literature in at least one individual affected with Zellweger spectrum disorder in a homozygous individual from a consanguieous Saudi Arabian family (e.g. Alfares_2017). However, the frequency of the variant in control chromosomes in the Middle Eastern subpopulation was measured at 0.003505 in 5706 chromosomes (gnomAD v4), therefore, this report does 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. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 31831025, 25182519). ClinVar contains an entry for this variant (Variation ID: 167445). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Zellweger spectrum disorders

Uncertain:1Benign:1

Jun 18, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.627G>A (p.M209I) alteration is located in exon 5 (coding exon 5) of the PEX1 gene. This alteration results from a G to A substitution at nucleotide position 627, causing the methionine (M) at amino acid position 209 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Heimler syndrome 1

Uncertain:1

Sep 10, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.57

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.027

T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.52

T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.0

L;.

PhyloP100

-0.20

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.15

Sift

Benign

0.18

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0010

B;.

Vest4

0.045

MutPred

0.33

Gain of catalytic residue at M209 (P = 0.0142);Gain of catalytic residue at M209 (P = 0.0142);

MVP

0.56

MPC

0.18

ClinPred

0.013

GERP RS

1.3

Varity_R

0.026

gMVP

0.18

Mutation Taster

=15/85

disease causing

(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