rs267608186
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_002857.4(PEX19):c.763_764insA(p.Met255AsnfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000246 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PEX19
NM_002857.4 frameshift
NM_002857.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.05
Genes affected
PEX19 (HGNC:9713): (peroxisomal biogenesis factor 19) This gene is necessary for early peroxisomal biogenesis. It acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. These disorders have at least 14 complementation groups, with more than one phenotype being observed for some complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of Zellweger syndrome (ZWS), as well as peroxisome biogenesis disorder complementation group 14 (PBD-CG14), which is also known as PBD-CGJ. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 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;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PEX19 | NM_002857.4 | c.763_764insA | p.Met255AsnfsTer25 | frameshift_variant | 6/8 | ENST00000368072.10 | |
| PEX19 | NM_001193644.1 | c.763_764insA | p.Met255AsnfsTer29 | frameshift_variant | 6/8 | ||
| PEX19 | NR_036492.2 | n.662_663insA | non_coding_transcript_exon_variant | 5/7 | |||
| PEX19 | NR_036493.2 | n.686_687insA | non_coding_transcript_exon_variant | 5/7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PEX19 | ENST00000368072.10 | c.763_764insA | p.Met255AsnfsTer25 | frameshift_variant | 6/8 | 1 | NM_002857.4 | P1 |
Frequencies
GnomAD3 genomes 0.00 AC: 2AN: 152216Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 251020Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135660
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461424Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727024
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GnomAD4 genome 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Peroxisome biogenesis disorder 12A (Zellweger) Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2021 | This variant is also known as PEX19A764ins. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 9217). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 10051604). This variant is present in population databases (rs267608186, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Met255Asnfs*25) in the PEX19 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the PEX19 protein. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 02, 1999 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at