rs189569984

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001134363.3(RBM20):c.1364C>T(p.Ser455Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00703 in 1,551,030 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S455S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 54 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:18

Conservation

PhyloP100: 5.08

Publications

18 publications found

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 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

RBM20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 10-110784367-C-T is Benign according to our data. Variant chr10-110784367-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00538 (819/152264) while in subpopulation NFE AF = 0.00782 (532/68016). AF 95% confidence interval is 0.00727. There are 4 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 819 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.1364C>T	p.Ser455Leu	missense_variant	Exon 4 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1199C>T	p.Ser400Leu	missense_variant	Exon 4 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.980C>T	p.Ser327Leu	missense_variant	Exon 4 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.980C>T	p.Ser327Leu	missense_variant	Exon 4 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.1364C>T	p.Ser455Leu	missense_variant	Exon 4 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.1364C>T	p.Ser455Leu	missense_variant	Exon 4 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

818

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00782

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00560

AC:

862

AN:

153884

AF XY:

0.00529

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.00672

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000982

Gnomad NFE exome

AF:

0.00781

Gnomad OTH exome

AF:

0.00923

GnomAD4 exome

AF:

0.00721

AC:

10086

AN:

1398766

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

4843

AN XY:

689922

show subpopulations

African (AFR)

AF:

0.00133

AC:

AN:

31590

American (AMR)

AF:

0.00655

AC:

234

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

486

AN:

25180

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35734

South Asian (SAS)

AF:

0.000530

AC:

AN:

79180

European-Finnish (FIN)

AF:

0.000975

AC:

AN:

49256

Middle Eastern (MID)

AF:

0.000920

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.00813

AC:

8766

AN:

1078736

Other (OTH)

AF:

0.00797

AC:

462

AN:

57958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

446

891

1337

1782

2228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00538

AC:

819

AN:

152264

Hom.:

Cov.:

AF XY:

0.00510

AC XY:

380

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41542

American (AMR)

AF:

0.00666

AC:

102

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00782

AC:

532

AN:

68016

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00719

Hom.:

Bravo

AF:

0.00562

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.0104

AC:

ExAC

AF:

0.00422

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 26, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RBM20 c.1364C>T (p.Ser455Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 153884 control chromosomes, including 5 homozygotes (gnomAD). The variant was observed with even higher frequency within Non-Finnish European control individuals (0.0078) that is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as benign (4x) / likely benign (2x). Based on the evidence outlined above, the variant was classified as benign. -

Mar 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser455Leu in exon 4 of RBM20: This variant has been reported in one individual with DCM and was absent in 1000 Caucasian and 200 African American control chro mosomes (Refaat 2011). However, this variant is not expected to have clinical si gnificance because it has been identified in 1.1% (27/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 26, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1DD

Benign:4

Oct 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy

Benign:2

Oct 19, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RBM20: BP4, BS2 -

Long QT syndrome

Benign:1

May 15, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 03, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.64

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.42

PhyloP100

5.1

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.051

Vest4

0.43

MVP

0.57

ClinPred

0.039

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.58

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over