rs757389650
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001134363.3(RBM20):c.3616G>A(p.Glu1206Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,540,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
RBM20
NM_001134363.3 missense
NM_001134363.3 missense
Scores
1
8
7
Clinical Significance
Conservation
PhyloP100: 5.19
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.22480199).
BS2
?
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.3616G>A | p.Glu1206Lys | missense_variant | 14/14 | ENST00000369519.4 | |
RBM20 | XM_017016103.3 | c.3451G>A | p.Glu1151Lys | missense_variant | 14/14 | ||
RBM20 | XM_017016104.3 | c.3232G>A | p.Glu1078Lys | missense_variant | 14/14 | ||
RBM20 | XM_047425116.1 | c.3232G>A | p.Glu1078Lys | missense_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.3616G>A | p.Glu1206Lys | missense_variant | 14/14 | 1 | NM_001134363.3 | P1 | |
RBM20 | ENST00000465774.2 | n.557G>A | non_coding_transcript_exon_variant | 2/2 | 4 | ||||
RBM20 | ENST00000480343.2 | n.249G>A | non_coding_transcript_exon_variant | 3/3 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152232Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000467 AC: 7AN: 149856Hom.: 0 AF XY: 0.0000251 AC XY: 2AN XY: 79700
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GnomAD4 exome AF: 0.0000382 AC: 53AN: 1388374Hom.: 0 Cov.: 28 AF XY: 0.0000350 AC XY: 24AN XY: 685420
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1DD Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 18, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2024 | Variant summary: RBM20 c.3616G>A (p.Glu1206Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 149856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3616G>A has been reported in the literature in one individual affected with Dilated Cardiomyopathy, without strong evidence for causality (Refaat_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. One publication reports experimental evidence evaluating an impact on mouse protein function, however, does not allow convincing conclusions about the variant effect (Murayama_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29895960, 22004663). ClinVar contains an entry for this variant (Variation ID: 418455). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Sep 19, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2020 | Observed in a patient with DCM in the published literature (Rafaat et al., 2012); Published functional studies are inconclusive in determining a damaging effect (Murayama et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 418455; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22004663, 30547036, 29895960) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2019 | The p.E1206K variant (also known as c.3616G>A), located in coding exon 14 of the RBM20 gene, results from a G to A substitution at nucleotide position 3616. The glutamic acid at codon 1206 is replaced by lysine, an amino acid with similar properties. This variant was detected in a dilated cardiomyopathy cohort; however, details were limited (Refaat MM et al. Heart Rhythm, 2012 Mar;9:390-6). One study of the equivalent variant in a mouse expression vector did not indicate a significant impact on the RBM20 properties studied (Murayama R et al. Sci Rep, 2018 Jun;8:8970). This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Vest4
MVP
ClinPred
T
GERP RS
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