rs1060503412

Positions:

• chr10-110781859-G-A

Variant summary

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

The NM_001134363.3(RBM20):​c.1250G>A​(p.Cys417Tyr) variant causes a missense 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C417C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.54

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, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1250G>A	p.Cys417Tyr	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1085G>A	p.Cys362Tyr	missense_variant	2/14
RBM20	XM_017016104.3	c.866G>A	p.Cys289Tyr	missense_variant	2/14
RBM20	XM_047425116.1	c.866G>A	p.Cys289Tyr	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1250G>A	p.Cys417Tyr	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RBM20-related disease. This sequence change replaces cysteine with tyrosine at codon 417 of the RBM20 protein (p.Cys417Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. 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: "Not Scored"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Apr 06, 2017

p.Cys417Tyr (c.1250G>A) in exon 2 of the RBM20 gene (NM_001134363.2) Chromosome location 10:112541617 G / A Given the lack of case data we consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). To our knowledge, this variant has not been reported in the literature in association with disease. It has not been reported to ClinVar by any lab as of 4/6/2017. This is a conservative amino acid change, replacing a polar Cysteine with a polar Tyrosine, albeit with a bulkier side-chain. The Cysteine at this location is absolutely conserved across ~100 vertebrate species for which we have data. The variant is NOT located in exon 9, which is a hotspot where disease-causing variants in RBM20 have been found. According to the test report: "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: "Not Scored"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). There are no variants listed as Likely Pathogenic or Pathogenic in ClinVar within 10 amino acids in either direction. There is no variation at codon 417 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The exome coverage at this and surrounding nucleotides appears to be poor, however. At this location, only 65% of exome participants are covered at even 1x. There is good coverage of at least 30x for approximately 60% of participants. For the genome group, coverage is above 15x for almost all participants. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MutPred		0.67		Gain of catalytic residue at I416 (P = 0.0344);
MVP		0.87
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.89

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: rs1060503412; hg19: chr10-112541617;