rs1554898987

Variant names:

• chr10-110781625-G-A
• rs1554898987
• NM_001134363.3:c.1016G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001134363.3(RBM20):​c.1016G>A​(p.Trp339*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.79
• 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 12 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 10-110781625-G-A is Pathogenic according to our data. Variant chr10-110781625-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520425.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1016G>A	p.Trp339*	stop_gained	Exon 2 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.851G>A	p.Trp284*	stop_gained	Exon 2 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.632G>A	p.Trp211*	stop_gained	Exon 2 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.632G>A	p.Trp211*	stop_gained	Exon 2 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1016G>A	p.Trp339*	stop_gained	Exon 2 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.1016G>A	p.Trp339*	stop_gained	Exon 2 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1DD Pathogenic:1

Feb 20, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		7.8
Vest4		0.90
GERP RS		5.3
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs1554898987; hg19: chr10-112541383;