rs371116877

chr10-110812894-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001134363.3(RBM20):c.2497A>G(p.Arg833Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,463,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08344361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2497A>G	p.Arg833Gly	missense_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2332A>G	p.Arg778Gly	missense_variant	9/14
RBM20	XM_017016104.3	c.2113A>G	p.Arg705Gly	missense_variant	9/14
RBM20	XM_047425116.1	c.2113A>G	p.Arg705Gly	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2497A>G	p.Arg833Gly	missense_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 6 AN: 1311662 Hom.: 0 Cov.: 32 AF XY: 0.00000470 AC XY: 3 AN XY: 637736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000481

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0000409 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 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) performed at Invitae indicates that this missense variant is not expected to disrupt RBM20 protein function. ClinVar contains an entry for this variant (Variation ID: 470601). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is present in population databases (rs371116877, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 833 of the RBM20 protein (p.Arg833Gly). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The p.R833G variant (also known as c.2497A>G), located in coding exon 9 of the RBM20 gene, results from an A to G substitution at nucleotide position 2497. The arginine at codon 833 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	0.55	D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Vest4		0.094
MVP		0.52
ClinPred		0.28	T
GERP RS		2.0
gMVP		0.13

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

Other links and lift over

dbSNP: rs371116877; hg19: chr10-112572652;