rs762353654
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_020964.3(EPG5):āc.2407T>Cā(p.Tyr803His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,578,736 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 (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000042 ( 0 hom. )
Consequence
EPG5
NM_020964.3 missense
NM_020964.3 missense
Scores
8
6
4
Clinical Significance
Conservation
PhyloP100: 8.22
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.806
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPG5 | NM_020964.3 | c.2407T>C | p.Tyr803His | missense_variant | 12/44 | ENST00000282041.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPG5 | ENST00000282041.11 | c.2407T>C | p.Tyr803His | missense_variant | 12/44 | 1 | NM_020964.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000906 AC: 2AN: 220678Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 120220
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GnomAD4 exome AF: 0.00000421 AC: 6AN: 1426510Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3AN XY: 707898
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Vici syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 2018 | This sequence change replaces tyrosine with histidine at codon 803 of the EPG5 protein (p.Tyr803His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs762353654, ExAC 0.007%). This variant has not been reported in the literature in individuals with EPG5-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;D
Vest4
MutPred
Loss of stability (P = 0.0591);Loss of stability (P = 0.0591);
MVP
MPC
ClinPred
D
GERP RS
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