rs1185476843

Variant names:

• chr10-110831061-G-A
• rs1185476843
• NM_001134363.3:c.3452G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110831061-G-A
• chr10-110831061-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001134363.3(RBM20):​c.3452G>A​(p.Gly1151Glu) variant causes a missense, splice region 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. 13/22 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G1151A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• 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), 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-110831061-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520538.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.3452G>A	p.Gly1151Glu	missense splice_region	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.3452G>A	p.Gly1151Glu	missense splice_region	Exon 13 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.3482G>A	p.Gly1161Glu	missense splice_region	Exon 13 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.3452G>A	p.Gly1151Glu	missense splice_region	Exon 13 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000652 AC: 1 AN: 153450 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.028	T
PhyloP100		9.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.96
MutPred		0.56		Loss of sheet (P = 7e-04)
MVP		0.86
ClinPred		0.98	D
GERP RS		5.4
gMVP		0.85
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.020		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: rs1185476843; hg19: chr10-112590819; COSMIC: COSV104681923; COSMIC: COSV104681923;