rs727503387

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001134363.3(RBM20):c.1418C>T(p.Ala473Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,550,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign 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. A473T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.114236474).

BP6

Variant 10-110784421-C-T is Benign according to our data. Variant chr10-110784421-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RBM20	NM_001134363.3 linkuse as main transcript	c.1418C>T	p.Ala473Val	missense_variant	4/14	ENST00000369519.4
RBM20	XM_017016103.3 linkuse as main transcript	c.1253C>T	p.Ala418Val	missense_variant	4/14
RBM20	XM_017016104.3 linkuse as main transcript	c.1034C>T	p.Ala345Val	missense_variant	4/14
RBM20	XM_047425116.1 linkuse as main transcript	c.1034C>T	p.Ala345Val	missense_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4 linkuse as main transcript	c.1418C>T	p.Ala473Val	missense_variant	4/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000130

AC:

AN:

153870

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81632

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000786

AC:

AN:

1398812

Hom.:

Cov.:

AF XY:

0.00000870

AC XY:

AN XY:

689936

show subpopulations

Gnomad4 AFR exome

AF:

0.000348

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2014

The Ala473Val variant in RBM20 has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Alanine (Ala) at position 473 is not conserved in mammals or evolutionarily distant species and the change to valine (Val) is present in horse, suggesting that this variant may be tolerated . Additional computational prediction tools suggest that the Ala473Val variant m ay not impact the protein, though this information is not predictive enough to r ule out pathogenicity. In summary, the clinical significance of the Ala473Val va riant is uncertain. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The p.A473V variant (also known as c.1418C>T), located in coding exon 4 of the RBM20 gene, results from a C to T substitution at nucleotide position 1418. The alanine at codon 473 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.78

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.53

MutationTaster

Benign

0.99

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.21

Sift4G

Benign

0.43

Vest4

0.070

MVP

0.37

ClinPred

0.11

GERP RS

4.1

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over