chr15-25340164-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_130839.5(UBE3A):c.2419A>G(p.Thr807Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. T807M) has been classified as Uncertain significance.
Frequency
Consequence
NM_130839.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBE3A | NM_130839.5 | c.2419A>G | p.Thr807Ala | missense_variant | 12/13 | ENST00000648336.2 | |
SNHG14 | NR_146177.1 | n.18393-51432T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBE3A | ENST00000648336.2 | c.2419A>G | p.Thr807Ala | missense_variant | 12/13 | NM_130839.5 | P1 | ||
SNHG14 | ENST00000656420.1 | n.5456+61280T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461774Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727182
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Angelman syndrome Uncertain:3
Uncertain significance, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Jun 20, 2023 | The c.2359A>G p.Thr787Ala variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_Supporting). The p.Thr787Ala variant has been observed in multiple individuals with seizures, where at least 2 of these cases are known to be maternally inherited (Invitae internal data) (PS4_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Functional studies suggest p.Thr787Ala is a gain of function variant that increases UBE3A ubiquitin ligase activity (PMID: 34815418). However, as loss of function is the known mechanism of UBE3A-associated disease, this evidence has not been applied. In summary, the p.Thr787Ala variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_Supporting, PS4_Supporting, PP3). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 20, 2023 | 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 are conflicting or provide insufficient evidence to determine the effect of this variant on UBE3A function (PMID: 34815418). 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 expected to disrupt UBE3A protein function. ClinVar contains an entry for this variant (Variation ID: 418562). This missense change has been observed in individual(s) with clinical features of UBE3A-related conditions (PMID: 34815418). This variant is present in population databases (rs374519603, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 787 of the UBE3A protein (p.Thr787Ala). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 22, 2023 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 05, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2023 | Published functional studies demonstrate that this variant increases UBE3A activity and accelerates ubiquitination activity (Weston et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26219744, 25884337, 25212744, 22670133, 19213023, 17940072, 17765640, 15263005, 8988171, 2309781, 34815418) - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2017 | Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at