10-110835878-C-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001134363.3(RBM20):āc.3584C>Gā(p.Ser1195Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000709 in 1,550,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001134363.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.3584C>G | p.Ser1195Cys | missense_variant | Exon 14 of 14 | ENST00000369519.4 | NP_001127835.2 | |
RBM20 | XM_017016103.3 | c.3419C>G | p.Ser1140Cys | missense_variant | Exon 14 of 14 | XP_016871592.1 | ||
RBM20 | XM_017016104.3 | c.3200C>G | p.Ser1067Cys | missense_variant | Exon 14 of 14 | XP_016871593.1 | ||
RBM20 | XM_047425116.1 | c.3200C>G | p.Ser1067Cys | missense_variant | Exon 14 of 14 | XP_047281072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.3584C>G | p.Ser1195Cys | missense_variant | Exon 14 of 14 | 1 | NM_001134363.3 | ENSP00000358532.3 | ||
RBM20 | ENST00000465774.2 | n.525C>G | non_coding_transcript_exon_variant | Exon 2 of 2 | 4 | |||||
RBM20 | ENST00000480343.2 | n.217C>G | non_coding_transcript_exon_variant | Exon 3 of 3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000662 AC: 1AN: 150986Hom.: 0 AF XY: 0.0000124 AC XY: 1AN XY: 80330
GnomAD4 exome AF: 0.00000501 AC: 7AN: 1398344Hom.: 0 Cov.: 30 AF XY: 0.00000435 AC XY: 3AN XY: 689704
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1DD Uncertain:2
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1195 of the RBM20 protein (p.Ser1195Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. ClinVar contains an entry for this variant (Variation ID: 470613). 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. 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. -
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not provided Uncertain:1
p.Ser1195Cys (c.3584C>G) in exon 14 of the RBM20 gene (NM_001134363.2; chr10 112595636 C>G) We have seen this in a patient with familial dilated cardiomyopathy who also has a TTN variant in the I band. SCICD Classification: variant of uncertain significance based on absence in the general population and lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: There is strong evidence implicating this gene in this disease. Region-level evidence: Per ongoing research by Dr. Victoria Parikh in our group, there are several regions of RBM20 that are enriched for variation in cases vs. the general population. However, this region has a low level of variation in case and extremely low to no variation in controls, making it under-powered for statistical comparisons. This is further complicated by a unusually low coverage in control/population frequency databases like ExAC. Case data (not including our patient): none that we or the genetic testing lab could find ClinVar: not present Segregation data: none reported In silico data: Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Not Scored"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0")." Population data: Highest MAF in non-Finnish European population: 0.001839%. Note this is has wide error bars given it is due to 1/54374 alleles. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at