chr10-110812306-A-G

Position:

• chr10-110812306-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001134363.3(RBM20):​c.1909A>G​(p.Ser637Gly) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S637N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest RS (size 27) in uniprot entity RBM20_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) 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 chr10-110812307-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 10-110812306-A-G is Pathogenic according to our data. Variant chr10-110812306-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 272.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1909A>G	p.Ser637Gly	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1744A>G	p.Ser582Gly	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1525A>G	p.Ser509Gly	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1525A>G	p.Ser509Gly	missense_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1909A>G	p.Ser637Gly	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2019

The p.S637G variant (also known as c.1909A>G), located in coding exon 9 of the RBM20 gene, results from an A to G substitution at nucleotide position 1909. The serine at codon 637 is replaced by glycine, an amino acid with similar properties. This variant has been reported in individuals with dilated cardiomyopathy (DCM) and segregated with disease in three affected relatives from one family (Brauch KM et al. J. Am. Coll. Cardiol., 2009 Sep;54:930-41; Millat G et al. Eur J Med Genet Aug;54:e570-5). This variant was also confirmed as de novo in one individual with DCM and left ventricular non-compaction (LVNC) (Sun Q et al. Pediatr Invest., 2020 Mar; 4:11-16). In addition, this alteration has been noted as occurring in the RS-rich hot spot region, and an in vitro study suggested this alteration may result in altered protein function (Guo W et al. Nat Med. 2012;18:766-73). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2019

Reported in association with cardiomyopathy (Brauch et al., 2009; Millat et al., 2011; Parikh et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22466703, 19712804, 21846512, 30871351, 32840935, 32851336) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.86	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Vest4		0.82
MutPred		0.70		Loss of phosphorylation at S637 (P = 6e-04);
MVP		0.91
ClinPred		0.92	D
GERP RS		5.7
gMVP		0.73

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: rs267607005; hg19: chr10-112572064;