chr7-92528434-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000466.3(PEX1):āc.2T>Cā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000107 in 1,587,658 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 Pathogenic (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.000011 ( 0 hom. )
Consequence
PEX1
NM_000466.3 start_lost
NM_000466.3 start_lost
Scores
8
4
3
Clinical Significance
Conservation
PhyloP100: 3.87
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 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000466.3 (PEX1) was described as [Likely_pathogenic] in ClinVar as 189106
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-92528434-A-G is Pathogenic according to our data. Variant chr7-92528434-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 371746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92528434-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.2T>C | p.Met1? | start_lost | 1/24 | ENST00000248633.9 | |
PEX1 | NM_001282677.2 | c.2T>C | p.Met1? | start_lost | 1/23 | ||
PEX1 | XM_047420472.1 | c.2T>C | p.Met1? | start_lost | 1/23 | ||
PEX1 | NM_001282678.2 | c.-658T>C | 5_prime_UTR_variant | 1/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.2T>C | p.Met1? | start_lost | 1/24 | 1 | NM_000466.3 | P1 | |
PEX1 | ENST00000428214.5 | c.2T>C | p.Met1? | start_lost | 1/23 | 1 | |||
PEX1 | ENST00000438045.5 | c.2T>C | p.Met1? | start_lost | 1/21 | 2 | |||
PEX1 | ENST00000484913.5 | n.6T>C | non_coding_transcript_exon_variant | 1/24 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000200 AC: 4AN: 199938Hom.: 0 AF XY: 0.00000913 AC XY: 1AN XY: 109528
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GnomAD4 exome AF: 0.0000111 AC: 16AN: 1435574Hom.: 0 Cov.: 31 AF XY: 0.00000983 AC XY: 7AN XY: 711776
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74306
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Zellweger spectrum disorders Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2022 | This sequence change affects the initiator methionine of the PEX1 mRNA. The next in-frame methionine is located at codon 209. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371746). Disruption of the initiator codon has been observed in individuals with Zellweger spectrum disorder (PMID: 21031596, 28468868). This variant is present in population databases (rs766020928, gnomAD 0.01%). - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 27, 2016 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Peroxisome biogenesis disorder type 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 10, 2020 | Variant summary: PEX1 c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 199938 control chromosomes (gnomAD). c.2T>C has been reported in the literature in multiple homozygous individuals affected with Zellweger Syndrome (ie. Ebberink_2010, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder 1B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 27, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
0.98
.;D;.
Vest4
MutPred
Loss of stability (P = 0.0188);Loss of stability (P = 0.0188);Loss of stability (P = 0.0188);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at