chr10-110797578-A-G

Variant names:

• chr10-110797578-A-G
• rs1309738508
• NM_001134363.3:c.1598A>G

Variant summary

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

The NM_001134363.3(RBM20):​c.1598A>G​(p.Asn533Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35050875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1598A>G	p.Asn533Ser	missense_variant	Exon 6 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1433A>G	p.Asn478Ser	missense_variant	Exon 6 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1214A>G	p.Asn405Ser	missense_variant	Exon 6 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1214A>G	p.Asn405Ser	missense_variant	Exon 6 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1598A>G	p.Asn533Ser	missense_variant	Exon 6 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.1598A>G	p.Asn533Ser	missense_variant	Exon 6 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Oct 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with serine at codon 533 of the RBM20 protein (p.Asn533Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RBM20-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Pathogenic	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.30	T
PhyloP100		4.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.27
Sift	Benign	0.031	D
Sift4G	Uncertain	0.024	D
Vest4		0.37
MutPred		0.33		Loss of stability (P = 0.1465);
MVP		0.74
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.46
Mutation Taster		=79/21	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: rs1309738508; hg19: chr10-112557336;