chr7-92487486-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_000466.3(PEX1):c.3823C>T(p.Arg1275Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,594,348 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000049 ( 0 hom. )
Consequence
PEX1
NM_000466.3 stop_gained
NM_000466.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.03
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00753 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.3823C>T | p.Arg1275Ter | stop_gained | 24/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.3823C>T | p.Arg1275Ter | stop_gained | 24/24 | 1 | NM_000466.3 | P1 | |
ENST00000658444.1 | n.575-3757G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152054Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1
AN:
152054
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248532Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134352
GnomAD3 exomes
AF:
AC:
3
AN:
248532
Hom.:
AF XY:
AC XY:
2
AN XY:
134352
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000485 AC: 7AN: 1442294Hom.: 0 Cov.: 25 AF XY: 0.00000418 AC XY: 3AN XY: 718318
GnomAD4 exome
AF:
AC:
7
AN:
1442294
Hom.:
Cov.:
25
AF XY:
AC XY:
3
AN XY:
718318
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152054Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74260
GnomAD4 genome
?
AF:
AC:
1
AN:
152054
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74260
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
1
Asia WGS
AF:
AC:
4
AN:
3452
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Zellweger spectrum disorders Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 17, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | This sequence change creates a premature translational stop signal (p.Arg1275*) in the PEX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the PEX1 protein. 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 variant has not been reported in the literature in individuals affected with PEX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 555569). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2021 | Variant summary: PEX1 c.3823C>T (p.Arg1275X) results in a premature termination codon in exon 24 (i.e. in the last exon) of the gene that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein. The variant is predicted to remove 9 amino-acids from the C-terminal end of the protein, in the gene PEX1 for which loss-of-function is a known mechanism of disease. The variant allele was found at a frequency of 1.2e-05 in 248532 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3823C>T in individuals affected with Zellweger Syndrome (ZS) and no experimental evidence demonstrating its impact on protein function have been reported. A truncating variant (i.e. c.3750G>A (p.Trp1250*)) upstream from this position have been reported in homozygous individuals affected with an attenuated phenotype representing the milder end of the ZS spectrum (PMID 26387595), and functional studies confirmed the hypomorphic effect of this variant (PMID 26387595). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, although the variant is unlikely to cause a severe ZS phenotype, a potential hypomorphic effect resulting from a partially functional protein cannot be excluded, therefore the variant was classified as uncertain significance. - |
Peroxisome biogenesis disorder 1A (Zellweger) Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 12, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at