rs200754523
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020964.3(EPG5):c.6839C>T(p.Ala2280Val) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2280T) has been classified as Uncertain significance.
Frequency
Consequence
NM_020964.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPG5 | NM_020964.3 | c.6839C>T | p.Ala2280Val | missense_variant | 40/44 | ENST00000282041.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPG5 | ENST00000282041.11 | c.6839C>T | p.Ala2280Val | missense_variant | 40/44 | 1 | NM_020964.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000762 AC: 19AN: 249296Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135254
GnomAD4 exome AF: 0.000114 AC: 167AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000921 AC XY: 67AN XY: 727244
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74464
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2023 | The c.6839C>T (p.A2280V) alteration is located in exon 40 (coding exon 40) of the EPG5 gene. This alteration results from a C to T substitution at nucleotide position 6839, causing the alanine (A) at amino acid position 2280 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Vici syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2280 of the EPG5 protein (p.Ala2280Val). This variant is present in population databases (rs200754523, gnomAD 0.02%). 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: 534598). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EPG5 protein function with a negative predictive value of 80%. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at