7-92517373-G-T

Variant names:

Variant summary

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

The NM_000466.3(PEX1):c.1142C>A(p.Ala381Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,242 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A381V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0075 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 11 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.24

Publications

2 publications found

Variant links:

COSMIC-nc: COSV104373606

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005811721).

BP6

Variant 7-92517373-G-T is Benign according to our data. Variant chr7-92517373-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00749 (1137/151872) while in subpopulation AFR AF = 0.0262 (1086/41432). AF 95% confidence interval is 0.0249. There are 14 homozygotes in GnomAd4. There are 500 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.1142C>A	p.Ala381Asp	missense_variant	Exon 5 of 24	ENST00000248633.9	NP_000457.1	O43933-1
PEX1	NM_001282677.2 link	c.1142C>A	p.Ala381Asp	missense_variant	Exon 5 of 23		NP_001269606.1	O43933A0A0C4DG33
PEX1	NM_001282678.2 link	c.518C>A	p.Ala173Asp	missense_variant	Exon 5 of 24		NP_001269607.1	O43933B4DER6
PEX1	XM_047420472.1 link	c.1142C>A	p.Ala381Asp	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.1142C>A	p.Ala381Asp	missense_variant	Exon 5 of 24	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.00749

AC:

1137

AN:

151754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00296

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00180

AC:

452

AN:

251376

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.0254

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000770

AC:

1125

AN:

1461370

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

512

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.0285

AC:

953

AN:

33468

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111614

Other (OTH)

AF:

0.00161

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00749

AC:

1137

AN:

151872

Hom.:

Cov.:

AF XY:

0.00674

AC XY:

500

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.0262

AC:

1086

AN:

41432

American (AMR)

AF:

0.00295

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67956

Other (OTH)

AF:

0.00238

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00280

Hom.:

Bravo

AF:

0.00878

ESP6500AA

AF:

0.0277

AC:

122

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00245

AC:

297

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 29, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2015

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Zellweger spectrum disorders

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Benign:1

Jan 13, 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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

3.2

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.25

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.11

B;.

Vest4

0.29

MVP

0.76

MPC

0.25

ClinPred

0.026

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.57

Mutation Taster

=99/1

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