rs587780582
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_130839.5(UBE3A):c.770T>C(p.Leu257Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L257H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_130839.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBE3A | NM_130839.5 | c.770T>C | p.Leu257Pro | missense_variant | 6/13 | ENST00000648336.2 | |
SNHG14 | NR_146177.1 | n.18393-20192A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBE3A | ENST00000648336.2 | c.770T>C | p.Leu257Pro | missense_variant | 6/13 | NM_130839.5 | P1 | ||
SNHG14 | ENST00000656420.1 | n.5457-47384A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Angelman syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Feb 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2020 | For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with Angelman syndrome (PMID: 25212744). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 136205). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 237 of the UBE3A protein (p.Leu237Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at