10-110831154-G-C

Variant names:

• chr10-110831154-G-C
• rs563762318
• NM_001134363.3:c.3545G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001134363.3(RBM20):​c.3545G>C​(p.Arg1182Pro) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1182C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3545G>C	p.Arg1182Pro	missense_variant	Exon 13 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3380G>C	p.Arg1127Pro	missense_variant	Exon 13 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.3161G>C	p.Arg1054Pro	missense_variant	Exon 13 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.3161G>C	p.Arg1054Pro	missense_variant	Exon 13 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3545G>C	p.Arg1182Pro	missense_variant	Exon 13 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.3545G>C	p.Arg1182Pro	missense_variant	Exon 13 of 14			ENSP00000520684.1
RBM20	ENST00000471172.1	n.121G>C		non_coding_transcript_exon_variant	Exon 2 of 2	5
RBM20	ENST00000480343.2	n.178G>C		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Apr 26, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.061	D
PhyloP100		9.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.91
MutPred		0.39		Loss of MoRF binding (P = 0.01);
MVP		0.84
ClinPred		0.99	D
GERP RS		5.6
gMVP		0.79
Mutation Taster		=43/57	disease causing

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: rs563762318; hg19: chr10-112590912;