rs753102653
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_001134363.3(RBM20):c.3584C>A(p.Ser1195Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000246 in 1,550,564 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1195C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001134363.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.3584C>A | p.Ser1195Tyr | missense_variant | 14/14 | ENST00000369519.4 | |
RBM20 | XM_017016103.3 | c.3419C>A | p.Ser1140Tyr | missense_variant | 14/14 | ||
RBM20 | XM_017016104.3 | c.3200C>A | p.Ser1067Tyr | missense_variant | 14/14 | ||
RBM20 | XM_047425116.1 | c.3200C>A | p.Ser1067Tyr | missense_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.3584C>A | p.Ser1195Tyr | missense_variant | 14/14 | 1 | NM_001134363.3 | P1 | |
RBM20 | ENST00000465774.2 | n.525C>A | non_coding_transcript_exon_variant | 2/2 | 4 | ||||
RBM20 | ENST00000480343.2 | n.217C>A | non_coding_transcript_exon_variant | 3/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.000328 AC: 50AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000278 AC: 42AN: 150986Hom.: 0 AF XY: 0.000249 AC XY: 20AN XY: 80330
GnomAD4 exome AF: 0.000237 AC: 332AN: 1398344Hom.: 1 Cov.: 30 AF XY: 0.000268 AC XY: 185AN XY: 689704
GnomAD4 genome AF: 0.000328 AC: 50AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 14, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2023 | Reported in one patient with probable or definite statin-associated myopathy (Neroldov et al., 2016); Also reported individuals with left ventricular non-compaction (LVNC), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, additional cardiogenetic variants were identified in some cases (Verdonschot et al., 2020; Miszalski-Jamka et al., 2017; Akinrinade et al., 2015; Seidelman et al., 2017; van Lint et al., 2019; Jskelinen et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27296017, 32851336, 32880476, 26084686, 28087566, 30847666, 30775854, 28798025) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Dilated cardiomyopathy 1DD Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2023 | Variant summary: RBM20 c.3584C>A (p.Ser1195Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 150986 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3584C>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy or Left ventricular non-compaction (Miszalski-Jamka_2017, Verdonschot_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28798025, 32880476). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 06, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at