NM_001134363.3:c.3667G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001134363.3(RBM20):c.3667G>C(p.Glu1223Gln) variant causes a missense change. The variant allele was found at a frequency of 0.828 in 1,259,556 control chromosomes in the GnomAD database, including 437,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1223D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.75 ( 44456 hom., cov: 33)

Exomes 𝑓: 0.84 ( 392666 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.12

Publications

29 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.3003877E-7).

BP6

Variant 10-110835961-G-C is Benign according to our data. Variant chr10-110835961-G-C is described in ClinVar as [Benign]. Clinvar id is 44016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.3667G>C	p.Glu1223Gln	missense_variant	Exon 14 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.3502G>C	p.Glu1168Gln	missense_variant	Exon 14 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.3283G>C	p.Glu1095Gln	missense_variant	Exon 14 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.3283G>C	p.Glu1095Gln	missense_variant	Exon 14 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBM20	ENST00000369519.4 link	c.3667G>C	p.Glu1223Gln	missense_variant	Exon 14 of 14	1	NM_001134363.3	ENSP00000358532.3	Q5T481
RBM20	ENST00000718239.1 link	c.3667G>C	p.Glu1223Gln	missense_variant	Exon 14 of 14			ENSP00000520684.1
RBM20	ENST00000465774.2 link	n.608G>C		non_coding_transcript_exon_variant	Exon 2 of 2	4
RBM20	ENST00000480343.2 link	n.300G>C		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113647

AN:

152112

Hom.:

44459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.490

Gnomad AMI

AF:

0.925

Gnomad AMR

AF:

0.791

Gnomad ASJ

AF:

0.850

Gnomad EAS

AF:

0.788

Gnomad SAS

AF:

0.718

Gnomad FIN

AF:

0.862

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.866

Gnomad OTH

AF:

0.772

GnomAD2 exomes

AF:

0.803

AC:

110677

AN:

137800

AF XY:

0.802

show subpopulations

Gnomad AFR exome

AF:

0.469

Gnomad AMR exome

AF:

0.785

Gnomad ASJ exome

AF:

0.846

Gnomad EAS exome

AF:

0.801

Gnomad FIN exome

AF:

0.863

Gnomad NFE exome

AF:

0.867

Gnomad OTH exome

AF:

0.813

GnomAD4 exome

AF:

0.839

AC:

928605

AN:

1107326

Hom.:

392666

Cov.:

AF XY:

0.836

AC XY:

465058

AN XY:

556506

show subpopulations

African (AFR)

AF:

0.471

AC:

11835

AN:

25136

American (AMR)

AF:

0.780

AC:

25144

AN:

32256

Ashkenazi Jewish (ASJ)

AF:

0.845

AC:

19272

AN:

22794

East Asian (EAS)

AF:

0.766

AC:

25646

AN:

33474

South Asian (SAS)

AF:

0.718

AC:

50807

AN:

70778

European-Finnish (FIN)

AF:

0.864

AC:

42192

AN:

48834

Middle Eastern (MID)

AF:

0.760

AC:

3876

AN:

5102

European-Non Finnish (NFE)

AF:

0.866

AC:

710994

AN:

820964

Other (OTH)

AF:

0.809

AC:

38839

AN:

47988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

6787

13573

20360

27146

33933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.747

AC:

113681

AN:

152230

Hom.:

44456

Cov.:

AF XY:

0.746

AC XY:

55558

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.489

AC:

20299

AN:

41502

American (AMR)

AF:

0.791

AC:

12110

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.850

AC:

2950

AN:

3472

East Asian (EAS)

AF:

0.789

AC:

4080

AN:

5174

South Asian (SAS)

AF:

0.719

AC:

3474

AN:

4830

European-Finnish (FIN)

AF:

0.862

AC:

9136

AN:

10604

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.867

AC:

58938

AN:

68018

Other (OTH)

AF:

0.769

AC:

1628

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1301

2602

3903

5204

6505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.830

Hom.:

16732

Bravo

AF:

0.729

TwinsUK

AF:

0.876

AC:

3249

ALSPAC

AF:

0.859

AC:

3312

ESP6500AA

AF:

0.496

AC:

687

ESP6500EA

AF:

0.872

AC:

2776

ExAC

AF:

0.741

AC:

16396

Asia WGS

AF:

0.704

AC:

2450

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 13, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2013

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

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

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary dilated cardiomyopathy

Benign:1

Sep 27, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 11, 2015

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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

9.3e-7

MetaSVM

Benign

-0.92

PhyloP100

4.1

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.72

REVEL

Uncertain

0.33

Sift

Uncertain

0.0070

Sift4G

Benign

0.087

Vest4

0.032

ClinPred

0.014

GERP RS

5.2

gMVP

0.30

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

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NM_001134363.3:c.3667G>C

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