10-110799887-T-G

Variant names:

• chr10-110799887-T-G
• rs794729147
• NM_001134363.3:c.1769T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001134363.3(RBM20):​c.1769T>G​(p.Met590Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1769T>G	p.Met590Arg	missense_variant	Exon 7 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1604T>G	p.Met535Arg	missense_variant	Exon 7 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1385T>G	p.Met462Arg	missense_variant	Exon 7 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1385T>G	p.Met462Arg	missense_variant	Exon 7 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1769T>G	p.Met590Arg	missense_variant	Exon 7 of 14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399790 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 690366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Jul 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RBM20-related conditions. ClinVar contains an entry for this variant (Variation ID: 202060). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 590 of the RBM20 protein (p.Met590Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. -

not provided Uncertain:1

Apr 26, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Met590Arg (ATG>AGG): c.1769 T>G in exon 7 of the RBM20 gene (NM_001134363.1). The Met590Arg variant in the RBM20 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Met590Arg results in a non-conservative amino acid substitution of a non-polar Methionine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Met590Arg is probably damaging to the protein structure/function. The Met590Arg variant was not observed in approximately 2,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy. With the clinical and molecular information available at this time, we cannot definitively determine if Met590Arg is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). -

Cardiovascular phenotype Uncertain:1

Oct 19, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M590R variant (also known as c.1769T>G), located in coding exon 7 of the RBM20 gene, results from a T to G substitution at nucleotide position 1769. The methionine at codon 590 is replaced by arginine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.024	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.89
MutPred		0.67		Gain of disorder (P = 0.0441);
MVP		0.80
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs794729147; hg19: chr10-112559645;