rs727503386

Variant names:

• chr10-110784881-G-A
• rs727503386
• NM_001134363.3:c.1519G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001134363.3(RBM20):​c.1519G>A​(p.Gly507Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G507G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1519G>A	p.Gly507Arg	missense_variant	Exon 5 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1354G>A	p.Gly452Arg	missense_variant	Exon 5 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1135G>A	p.Gly379Arg	missense_variant	Exon 5 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1135G>A	p.Gly379Arg	missense_variant	Exon 5 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1519G>A	p.Gly507Arg	missense_variant	Exon 5 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.1519G>A	p.Gly507Arg	missense_variant	Exon 5 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly507Arg variant in RBM20 has not been reported in individuals with cardiom yopathy or in large population studies. Computational analyses are limited or un available for this variant. Additional information is needed to fully assess the clinical significance of the Gly507Arg variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.38	D
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.29	T
Vest4		0.38
MutPred		0.55		Gain of MoRF binding (P = 0.0235);
MVP		0.72
ClinPred		0.96	D
GERP RS		6.2
gMVP		0.66
Mutation Taster		=50/50

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: rs727503386; hg19: chr10-112544639;