rs143273433

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000466.3(PEX1):c.1249G>A(p.Asp417Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,567,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D417D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.24

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19716257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.1249G>A	p.Asp417Asn	missense_variant	Exon 6 of 24	ENST00000248633.9	NP_000457.1	O43933-1
PEX1	NM_001282677.2 link	c.1249G>A	p.Asp417Asn	missense_variant	Exon 6 of 23		NP_001269606.1	O43933A0A0C4DG33
PEX1	NM_001282678.2 link	c.625G>A	p.Asp209Asn	missense_variant	Exon 6 of 24		NP_001269607.1	O43933B4DER6
PEX1	XM_047420472.1 link	c.1249G>A	p.Asp417Asn	missense_variant	Exon 6 of 23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 link	c.1249G>A	p.Asp417Asn	missense_variant	Exon 6 of 24	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000196

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000114

AC:

AN:

244682

AF XY:

0.000136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000205

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000170

AC:

241

AN:

1415468

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

113

AN XY:

706022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32426

American (AMR)

AF:

0.000206

AC:

AN:

43720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25690

East Asian (EAS)

AF:

0.00

AC:

AN:

39318

South Asian (SAS)

AF:

0.00

AC:

AN:

82522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.000206

AC:

221

AN:

1075378

Other (OTH)

AF:

0.000187

AC:

AN:

58762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:

0.000132

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41412

American (AMR)

AF:

0.000196

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000180

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Zellweger spectrum disorders

Uncertain:2

Nov 14, 2017

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 417 of the PEX1 protein (p.Asp417Asn). This variant is present in population databases (rs143273433, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PEX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498412). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PEX1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Sep 26, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Jul 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1249G>A (p.D417N) alteration is located in exon 6 (coding exon 6) of the PEX1 gene. This alteration results from a G to A substitution at nucleotide position 1249, causing the aspartic acid (D) at amino acid position 417 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger)

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.044

.;T;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.5

.;M;.

PhyloP100

1.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.46

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.70

.;P;.

Vest4

0.36

MVP

0.89

MPC

0.17

ClinPred

0.13

GERP RS

5.0

Varity_R

0.069

gMVP

0.43

Mutation Taster

=97/3

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