rs542297252
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_001134363.3(RBM20):c.3517G>A(p.Glu1173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,551,588 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 1 hom. )
Consequence
RBM20
NM_001134363.3 missense
NM_001134363.3 missense
Scores
5
9
2
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
RBM20 (HGNC:27424): (RNA binding motif protein 20) This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000263 (4/152258) while in subpopulation SAS AF= 0.00083 (4/4820). AF 95% confidence interval is 0.000283. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 30 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.3517G>A | p.Glu1173Lys | missense_variant | 13/14 | ENST00000369519.4 | NP_001127835.2 | |
RBM20 | XM_017016103.3 | c.3352G>A | p.Glu1118Lys | missense_variant | 13/14 | XP_016871592.1 | ||
RBM20 | XM_017016104.3 | c.3133G>A | p.Glu1045Lys | missense_variant | 13/14 | XP_016871593.1 | ||
RBM20 | XM_047425116.1 | c.3133G>A | p.Glu1045Lys | missense_variant | 13/14 | XP_047281072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.3517G>A | p.Glu1173Lys | missense_variant | 13/14 | 1 | NM_001134363.3 | ENSP00000358532.3 | ||
RBM20 | ENST00000471172.1 | n.93G>A | non_coding_transcript_exon_variant | 2/2 | 5 | |||||
RBM20 | ENST00000480343.2 | n.150G>A | non_coding_transcript_exon_variant | 2/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000260 AC: 4AN: 153930Hom.: 0 AF XY: 0.0000367 AC XY: 3AN XY: 81672
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GnomAD4 exome AF: 0.0000214 AC: 30AN: 1399330Hom.: 1 Cov.: 30 AF XY: 0.0000304 AC XY: 21AN XY: 690176
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74450
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1DD Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2022 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RBM20 protein function. ClinVar contains an entry for this variant (Variation ID: 470612). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is present in population databases (rs542297252, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1173 of the RBM20 protein (p.Glu1173Lys). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Apr 01, 2021 | The p.Glu1173Lys variant in the RBM20 gene has not been previously reported in association with disease. • This variant has been identified in 4/22,770 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Computational tools predict that p.Glu1173Lys variant is deleterious; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Glu1173Lys variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 30, 2024 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2023 | The p.E1173K variant (also known as c.3517G>A), located in coding exon 13 of the RBM20 gene, results from a G to A substitution at nucleotide position 3517. The glutamic acid at codon 1173 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available 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
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
MutPred
Gain of ubiquitination at E1173 (P = 0.0198);
MVP
ClinPred
D
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