rs1555673890
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020964.3(EPG5):c.3789_3790insTATTGAAGGGGAATTGGTGATAAACTCT(p.Ala1264TyrfsTer2) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
EPG5
NM_020964.3 stop_gained, frameshift
NM_020964.3 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0430
Genes affected
EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 18-45913732-C-CAGAGTTTATCACCAATTCCCCTTCAATA is Pathogenic according to our data. Variant chr18-45913732-C-CAGAGTTTATCACCAATTCCCCTTCAATA is described in ClinVar as [Pathogenic]. Clinvar id is 466248.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPG5 | NM_020964.3 | c.3789_3790insTATTGAAGGGGAATTGGTGATAAACTCT | p.Ala1264TyrfsTer2 | stop_gained, frameshift_variant | 21/44 | ENST00000282041.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPG5 | ENST00000282041.11 | c.3789_3790insTATTGAAGGGGAATTGGTGATAAACTCT | p.Ala1264TyrfsTer2 | stop_gained, frameshift_variant | 21/44 | 1 | NM_020964.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249544Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135384
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727210
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Vici syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Ala1264Tyrfs*2) in the EPG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EPG5 are known to be pathogenic (PMID: 23222957, 23674064). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with EPG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 466248). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at