rs876657978

Variant names:

• chr10-110812680-G-GA
• rs876657978
• NM_001134363.3:c.2286dupA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001134363.3(RBM20):​c.2286dupA​(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 (★). 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
• Publications: 0 publications found

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]

RBM20 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1DD

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.2286dupA	p.Glu763ArgfsTer38	frameshift_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.2121dupA	p.Glu708ArgfsTer38	frameshift_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1902dupA	p.Glu635ArgfsTer38	frameshift_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1902dupA	p.Glu635ArgfsTer38	frameshift_variant	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.2286dupA	p.Glu763ArgfsTer38	frameshift_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.2286dupA	p.Glu763ArgfsTer38	frameshift_variant	Exon 9 of 14			ENSP00000520684.1

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

Apr 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6

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

Other links and lift over

dbSNP: rs876657978; hg19: chr10-112572438;