7-92493122-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000466.3(PEX1):c.3038G>A(p.Arg1013His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,589,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1013C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 7.69

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 links:

ENSG00000244055 (HGNC:):

ENSG00000244055 links:

GATAD1 (HGNC:29941): (GATA zinc finger domain containing 1) The protein encoded by this gene contains a zinc finger at the N-terminus, and is thought to bind to a histone modification site that regulates gene expression. Mutations in this gene have been associated with autosomal recessive dilated cardiomyopathy. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

GATAD1 Gene-Disease associations (from GenCC):

familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 2B
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GATAD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-92493123-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1069047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 7-92493122-C-T is Pathogenic according to our data. Variant chr7-92493122-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.3038G>A	p.Arg1013His	missense_variant	Exon 20 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.3038G>A	p.Arg1013His	missense_variant	Exon 20 of 24	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151312

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

248816

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000626

AC:

AN:

1438338

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33114

American (AMR)

AF:

0.00

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.0000775

AC:

AN:

25796

East Asian (EAS)

AF:

0.00

AC:

AN:

39288

South Asian (SAS)

AF:

0.00

AC:

AN:

83268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000548

AC:

AN:

1094430

Other (OTH)

AF:

0.0000168

AC:

AN:

59426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000132

AC:

AN:

151312

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73834

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41180

American (AMR)

AF:

0.00

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.0000953

AC:

AN:

10496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67772

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Zellweger spectrum disorders

Pathogenic:1

Nov 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1013 amino acid residue in PEX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27124789, 30561787). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt PEX1 protein function. ClinVar contains an entry for this variant (Variation ID: 551650). This missense change has been observed in individuals with Zellweger spectrum disorder (PMID: 16141001, 20952722). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1013 of the PEX1 protein (p.Arg1013His). -

Heimler syndrome 1

Pathogenic:1

Aug 29, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Uncertain:1

May 02, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

.;D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

.;M;.

PhyloP100

7.7

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.96

MutPred

0.96

.;Loss of disorder (P = 0.1357);.;

MVP

0.98

MPC

0.75

ClinPred

1.0

GERP RS

5.9

Varity_R

0.97

gMVP

0.82

Mutation Taster

=3/97

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over