chr10-110831173-G-C

Variant names:

• chr10-110831173-G-C
• rs1060503416
• NM_001134363.3:c.3564G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134363.3(RBM20):​c.3564G>C​(p.Arg1188Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R1188G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.69
• 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), 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37886816).

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.3564G>C	p.Arg1188Ser	missense	Exon 13 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.3564G>C	p.Arg1188Ser	missense	Exon 13 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.3594G>C	p.Arg1198Ser	missense	Exon 13 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.3564G>C	p.Arg1188Ser	missense	Exon 13 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398840 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689838

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.00 AC: 0 AN: 79214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078550

Other (OTH) AF: 0.00 AC: 0 AN: 57980

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1DD (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.57	T
PhyloP100		3.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Vest4		0.49
MutPred		0.25		Loss of MoRF binding (P = 0.0235)
MVP		0.58
ClinPred		0.93	D
GERP RS		4.7
gMVP		0.40
Mutation Taster		=76/24	polymorphism

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: rs1060503416; hg19: chr10-112590931;