rs397516596
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_001134363.3(RBM20):c.1633G>A(p.Val545Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,551,816 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 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
RBM20
NM_001134363.3 missense
NM_001134363.3 missense
Scores
4
3
9
Clinical Significance
Conservation
PhyloP100: 9.70
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=0.33877152).
BP6
?
Variant 10-110797613-G-A is Benign according to our data. Variant chr10-110797613-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43976.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr10-110797613-G-A is described in Lovd as [Likely_benign].
BS2
?
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.1633G>A | p.Val545Ile | missense_variant | 6/14 | ENST00000369519.4 | |
RBM20 | XM_017016103.3 | c.1468G>A | p.Val490Ile | missense_variant | 6/14 | ||
RBM20 | XM_017016104.3 | c.1249G>A | p.Val417Ile | missense_variant | 6/14 | ||
RBM20 | XM_047425116.1 | c.1249G>A | p.Val417Ile | missense_variant | 6/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.1633G>A | p.Val545Ile | missense_variant | 6/14 | 1 | NM_001134363.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152172Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000698 AC: 11AN: 157540Hom.: 0 AF XY: 0.0000721 AC XY: 6AN XY: 83232
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GnomAD4 exome AF: 0.000129 AC: 181AN: 1399526Hom.: 0 Cov.: 30 AF XY: 0.000132 AC XY: 91AN XY: 690256
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1DD Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2024 | Has been reported in individuals with cardiomyopathy who also harbored variants in other genes (PMID: 23396983, 24503780); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies in cardiomyocytes suggest that this variant has a wild-type nuclear localization, and does not affect splicing (PMID: 32840935); This variant is associated with the following publications: (PMID: 23396983, 25351510, 24503780, 32840935) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | The p.V545I variant (also known as c.1633G>A), located in coding exon 6 of the RBM20 gene, results from a G to A substitution at nucleotide position 1633. The valine at codon 545 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in cardiomyopathy cohorts; however, clinical details were limited (Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Pugh TJ et al. Genet Med, 2014 Aug;16:601-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 01, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of catalytic residue at L550 (P = 0.0332);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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