rs876657978

Positions:

• chr10-110812680-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001134363.3(RBM20):​c.2286dup​(p.Glu763ArgfsTer38) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R761R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2286dup	p.Glu763ArgfsTer38	frameshift_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2121dup	p.Glu708ArgfsTer38	frameshift_variant	9/14
RBM20	XM_017016104.3	c.1902dup	p.Glu635ArgfsTer38	frameshift_variant	9/14
RBM20	XM_047425116.1	c.1902dup	p.Glu635ArgfsTer38	frameshift_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2286dup	p.Glu763ArgfsTer38	frameshift_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 09, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu763fs variant in RBM20 has not been reported in individuals with cardiomyopathy and da ta from large population studies is insufficient to assess its frequency. This f rameshift variant is predicted to alter the protein?s amino acid sequence beginn ing at position 763 and lead to a premature termination codon 38 amino acids dow nstream. This alteration is then predicted to lead to a truncated or absent prot ein. The role of loss-of-function variants in the RBM20 gene is currently unclea r although data from animal models support that loss of function may lead to DCM (Guo 2012). In summary, while the available data suggest the p.Glu763fs variant may be disease-causing, additional information is required to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

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: rs876657978; hg19: chr10-112572438;