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rs149806989

Variant summary

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

The NM_000466.3(PEX1):c.547C>T(p.Arg183Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,500 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: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PEX1
NM_000466.3 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.25
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]

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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 7-92517968-G-A is Pathogenic according to our data. Variant chr7-92517968-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517968-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PEX1NM_000466.3 linkuse as main transcriptc.547C>T p.Arg183Ter stop_gained 5/24 ENST00000248633.9
PEX1NM_001282677.2 linkuse as main transcriptc.547C>T p.Arg183Ter stop_gained 5/23
PEX1XM_047420472.1 linkuse as main transcriptc.547C>T p.Arg183Ter stop_gained 5/23
PEX1NM_001282678.2 linkuse as main transcriptc.-78C>T 5_prime_UTR_variant 5/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PEX1ENST00000248633.9 linkuse as main transcriptc.547C>T p.Arg183Ter stop_gained 5/241 NM_000466.3 P1O43933-1
PEX1ENST00000428214.5 linkuse as main transcriptc.547C>T p.Arg183Ter stop_gained 5/231
PEX1ENST00000438045.5 linkuse as main transcriptc.274-4001C>T intron_variant 2 O43933-2
PEX1ENST00000484913.5 linkuse as main transcriptn.586C>T non_coding_transcript_exon_variant 5/242

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000805
AC:
2
AN:
248528
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000100
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1459500
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
725876
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000305
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 20, 2023- -
Zellweger spectrum disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 16, 2023This sequence change creates a premature translational stop signal (p.Arg183*) 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). This variant is present in population databases (rs149806989, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Zellweger syndrome (PMID: 19105186). ClinVar contains an entry for this variant (Variation ID: 371782). For these reasons, this variant has been classified as Pathogenic. -
Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 28, 2021- -
Peroxisome biogenesis disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 10, 2018Variant summary: PEX1 c.547C>T (p.Arg183X) 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; c.2916delA, p.Gly973fsX16). The variant allele was found at a frequency of 8.2e-06 in 244450 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (8.2e-06 vs 3.90e-03), allowing no conclusion about variant significance. The variant, c.547C>T, has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Yik_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Peroxisome biogenesis disorder 1B Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCounsylOct 11, 2016- -
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCounsylOct 11, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.53
Cadd
Pathogenic
35
Dann
Uncertain
1.0
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
A;A;D
Vest4
0.46
GERP RS
4.8

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.

Other links and lift over

dbSNP: rs149806989; hg19: chr7-92147282; API