10-110812297-C-G

Variant names:

• chr10-110812297-C-G
• rs796734066
• NM_001134363.3:c.1900C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001134363.3(RBM20):​c.1900C>G​(p.Arg634Gly) variant causes a missense change involving the alteration of a non-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. R634W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_001134363.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-110812297-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 411653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

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.1900C>G	p.Arg634Gly	missense	Exon 9 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.1900C>G	p.Arg634Gly	missense	Exon 9 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.1930C>G	p.Arg644Gly	missense	Exon 9 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.1900C>G	p.Arg634Gly	missense	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	0.78
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.62	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.95	D
PhyloP100		1.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.73
MutPred		0.43		Loss of MoRF binding (P = 0.016)
MVP		0.61
ClinPred		0.99	D
GERP RS		2.5
gMVP		0.77
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs796734066; hg19: chr10-112572055;