rs727504763

Variant names:

• chr10-110821880-CC-G
• rs727504763
• NM_001134363.3:c.3261_3262delCCinsG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001134363.3(RBM20):​c.3261_3262delCCinsG​(p.Ser1087ArgfsTer17) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 frameshift, missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 0.0640
• Publications: 2 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), G2P, Ambry Genetics
• 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 11 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
• PP5: Variant 10-110821880-CC-G is Pathogenic according to our data. Variant chr10-110821880-CC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179284.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.3261_3262delCCinsG	p.Ser1087ArgfsTer17	frameshift missense	Exon 11 of 14	NP_001127835.2	Q5T481

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.3261_3262delCCinsG	p.Ser1087ArgfsTer17	frameshift missense	Exon 11 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.3291_3292delCCinsG	p.Ser1097ArgfsTer17	frameshift missense	Exon 11 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.3261_3262delCCinsG	p.Ser1087ArgfsTer17	frameshift missense	Exon 11 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Cardiovascular phenotype (2)
-	1	-	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1DD (1)
-	1	-	not provided (1)
1	-	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064

Splicing

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

Other links and lift over

dbSNP: rs727504763; hg19: chr10-112581638;