chr7-92517406-A-AT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000466.3(PEX1):c.1108dupA(p.Ile370AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,449,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEX1
NM_000466.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -0.542

Publications

10 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-92517406-A-AT is Pathogenic according to our data. Variant chr7-92517406-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 644707.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.1108dupA	p.Ile370AsnfsTer2	frameshift_variant	Exon 5 of 24	ENST00000248633.9	NP_000457.1	O43933-1
PEX1	NM_001282677.2 link	c.1108dupA	p.Ile370AsnfsTer2	frameshift_variant	Exon 5 of 23		NP_001269606.1	O43933A0A0C4DG33
PEX1	NM_001282678.2 link	c.484dupA	p.Ile162AsnfsTer2	frameshift_variant	Exon 5 of 24		NP_001269607.1	O43933B4DER6
PEX1	XM_047420472.1 link	c.1108dupA	p.Ile370AsnfsTer2	frameshift_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.1108dupA	p.Ile370AsnfsTer2	frameshift_variant	Exon 5 of 24	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150700

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

244980

AF XY:

0.0000226

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000966

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1449922

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

721580

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33206

American (AMR)

AF:

0.00

AC:

AN:

44514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39472

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85798

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1102298

Other (OTH)

AF:

0.0000167

AC:

AN:

59918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150700

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73506

African (AFR)

AF:

0.00

AC:

AN:

41024

American (AMR)

AF:

0.00

AC:

AN:

15066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67614

Other (OTH)

AF:

0.00

AC:

AN:

2068

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Zellweger spectrum disorders

Pathogenic:2

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ile370Asnfs*2) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 16088892). This variant is also known as c.1108_1109insA. ClinVar contains an entry for this variant (Variation ID: 644707). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Nov 30, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Heimler syndrome 1

Pathogenic:1

Feb 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder

Pathogenic:1

Mar 04, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PEX1 c.1108dupA (p.Ile370AsnfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2097dupT (p.Ile700fsX42), c.2368C>T (p.Arg790X), and c.2916delA (p.Gly973fsX16)). The variant allele was found at a frequency of 1.7e-05 in 240452 control chromosomes (gnomAD). c.1108dupA has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Maxwell_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Pathogenic:1

Apr 28, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.54

Mutation Taster

=2/198

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over