rs727504859
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001134363.3(RBM20):c.2746G>A(p.Glu916Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
RBM20
NM_001134363.3 missense
NM_001134363.3 missense
Scores
2
7
7
Clinical Significance
Conservation
PhyloP100: 6.84
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-110821365-G-A is Pathogenic according to our data. Variant chr10-110821365-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179425.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.3548532). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.2746G>A | p.Glu916Lys | missense_variant | 11/14 | ENST00000369519.4 | NP_001127835.2 | |
RBM20 | XM_017016103.3 | c.2581G>A | p.Glu861Lys | missense_variant | 11/14 | XP_016871592.1 | ||
RBM20 | XM_017016104.3 | c.2362G>A | p.Glu788Lys | missense_variant | 11/14 | XP_016871593.1 | ||
RBM20 | XM_047425116.1 | c.2362G>A | p.Glu788Lys | missense_variant | 11/14 | XP_047281072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.2746G>A | p.Glu916Lys | missense_variant | 11/14 | 1 | NM_001134363.3 | ENSP00000358532.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 09, 2014 | The Glu916Lys variant in RBM20 has been identified by our laboratory in 1 indivi dual with DCM was found to segregate with disease in 5 affected individuals, inc luding 4 obligate carriers. This variant was was absent from large population s tudies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. While pathogenic variant s in RBM20 have been reported in cases of DCM within exon 9 (Brauch 2009, Li 201 0), the impact of variants in other regions is currently unclear. In summary, al though additional studies are required to fully establish its clinical significa nce, the segregation with and presentation of disease in this family support tha t the Glu916Lys variant is likely pathogenic. - |
Dilated cardiomyopathy 1DD Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2021 | 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. 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 RBM20 protein function. ClinVar contains an entry for this variant (Variation ID: 179425). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 916 of the RBM20 protein (p.Glu916Lys). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
MutPred
Gain of ubiquitination at E916 (P = 0.0066);
MVP
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at