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):ā€‹c.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

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000050 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

3
11
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.96
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBM20NM_001134363.3 linkc.3584C>G p.Ser1195Cys missense_variant Exon 14 of 14 ENST00000369519.4 NP_001127835.2 Q5T481
RBM20XM_017016103.3 linkc.3419C>G p.Ser1140Cys missense_variant Exon 14 of 14 XP_016871592.1
RBM20XM_017016104.3 linkc.3200C>G p.Ser1067Cys missense_variant Exon 14 of 14 XP_016871593.1
RBM20XM_047425116.1 linkc.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
RBM20ENST00000369519.4 linkc.3584C>G p.Ser1195Cys missense_variant Exon 14 of 14 1 NM_001134363.3 ENSP00000358532.3 Q5T481
RBM20ENST00000465774.2 linkn.525C>G non_coding_transcript_exon_variant Exon 2 of 2 4
RBM20ENST00000480343.2 linkn.217C>G non_coding_transcript_exon_variant Exon 3 of 3 4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000662
AC:
1
AN:
150986
Hom.:
0
AF XY:
0.0000124
AC XY:
1
AN XY:
80330
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000175
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000501
AC:
7
AN:
1398344
Hom.:
0
Cov.:
30
AF XY:
0.00000435
AC XY:
3
AN XY:
689704
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000649
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:2
Jun 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 03, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Oct 19, 2017
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: provider interpretation

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Uncertain
0.99
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Uncertain
0.74
D
MetaSVM
Uncertain
0.79
D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.7
D
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0050
D
Vest4
0.57
MutPred
0.33
Loss of disorder (P = 0.0197);
MVP
0.84
ClinPred
0.97
D
GERP RS
5.0
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753102653; hg19: chr10-112595636; COSMIC: COSV65703996; COSMIC: COSV65703996; API