rs61750409

Positions:

chr7-92506251-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000466.3(PEX1):c.1897C>T(p.Arg633*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000642 in 1,557,706 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

PEX1
NM_000466.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.53

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:

PEX1 (HGNC:):

PEX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 7-92506251-G-A is Pathogenic according to our data. Variant chr7-92506251-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92506251-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3 linkuse as main transcript	c.1897C>T	p.Arg633*	stop_gained	11/24	ENST00000248633.9	NP_000457.1	O43933-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 linkuse as main transcript	c.1897C>T	p.Arg633*	stop_gained	11/24	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151864

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251234

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135806

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000640

AC:

AN:

1405842

Hom.:

Cov.:

AF XY:

0.00000853

AC XY:

AN XY:

703070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000565

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PEX1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2023

The PEX1 c.1897C>T variant is predicted to result in premature protein termination (p.Arg633*). This variant has been reported in patients with PEX1-related disorders (Patient E-13 in Tamura et al. 2001. PubMed ID: 11439091; Abualsaud et al. 2020. PubMed ID: 32949114; Shamseldin et al. 2021. PubMed ID: 34645488; Rosewich et al. 2005. PubMed ID: 16141001). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92135565-G-A). Nonsense variants in PEX1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Zellweger spectrum disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 550841). This premature translational stop signal has been observed in individual(s) with PEX1-related conditions (PMID: 11439091). 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 sequence change creates a premature translational stop signal (p.Arg633*) 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: 9398847, 16086329, 16141001, 21031596, 26387595, 31831025). -

Heimler syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 29, 2023

- -

Peroxisome biogenesis disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 19, 2022

Variant summary: PEX1 c.1897C>T (p.Arg633X) 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. The variant allele was found at a frequency of 4e-06 in 251234 control chromosomes. c.1897C>T has been reported in the literature in individuals affected with Peroxisome Biogenesis Disorder/Zellweger syndrome (example, Piscosquito_2016, Rosewich_2005, Tamura_2001, Alshenaifi_2019). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Peroxisome biogenesis disorder 1A (Zellweger)

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

Vest4

0.94

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over