rs727504859

chr10-110821365-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001134363.3(RBM20):c.2746G>A(p.Glu916Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.84

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-110821365-G-A is Pathogenic according to our data. Variant chr10-110821365-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179425.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3548532).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2746G>A	p.Glu916Lys	missense_variant	11/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2581G>A	p.Glu861Lys	missense_variant	11/14
RBM20	XM_017016104.3	c.2362G>A	p.Glu788Lys	missense_variant	11/14
RBM20	XM_047425116.1	c.2362G>A	p.Glu788Lys	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2746G>A	p.Glu916Lys	missense_variant	11/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 09, 2014

The Glu916Lys variant in RBM20 has been identified by our laboratory in 1 indivi dual with DCM was found to segregate with disease in 5 affected individuals, inc luding 4 obligate carriers. This variant was was absent from large population s tudies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. While pathogenic variant s in RBM20 have been reported in cases of DCM within exon 9 (Brauch 2009, Li 201 0), the impact of variants in other regions is currently unclear. In summary, al though additional studies are required to fully establish its clinical significa nce, the segregation with and presentation of disease in this family support tha t the Glu916Lys variant is likely pathogenic. -

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2021

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: 179425). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 916 of the RBM20 protein (p.Glu916Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	0.85	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.017	D
Vest4		0.48
MutPred		0.33		Gain of ubiquitination at E916 (P = 0.0066);
MVP		0.64
ClinPred		0.97	D
GERP RS		4.7
gMVP		0.44

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: rs727504859; hg19: chr10-112581123;