rs397516593

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001134363.3(RBM20):c.128_130dupAGC(p.Gln43dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00133 in 1,525,996 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 36 hom. )

Consequence

RBM20
NM_001134363.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 3.99

Publications

1 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 -9 ACMG points.

BP6

Variant 10-110644576-T-TGCA is Benign according to our data. Variant chr10-110644576-T-TGCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43970.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000894 (135/151004) while in subpopulation SAS AF = 0.0253 (120/4740). AF 95% confidence interval is 0.0216. There are 3 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.128_130dupAGC	p.Gln43dup	disruptive_inframe_insertion	Exon 1 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.26+1142_26+1144dupAGC		intron_variant	Intron 1 of 13		XP_016871592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.128_130dupAGC	p.Gln43dup	disruptive_inframe_insertion	Exon 1 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.128_130dupAGC	p.Gln43dup	disruptive_inframe_insertion	Exon 1 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.000901

AC:

136

AN:

150884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0255

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.00393

AC:

476

AN:

121236

AF XY:

0.00520

show subpopulations

Gnomad AFR exome

AF:

0.000262

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00111

GnomAD4 exome

AF:

0.00138

AC:

1892

AN:

1374992

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1336

AN XY:

678152

show subpopulations

African (AFR)

AF:

0.000170

AC:

AN:

29416

American (AMR)

AF:

0.000176

AC:

AN:

34144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24486

East Asian (EAS)

AF:

0.00

AC:

AN:

34010

South Asian (SAS)

AF:

0.0228

AC:

1770

AN:

77626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41386

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

4182

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

1072710

Other (OTH)

AF:

0.00160

AC:

AN:

57032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

167

250

334

417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000894

AC:

135

AN:

151004

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

104

AN XY:

73762

show subpopulations

African (AFR)

AF:

0.000292

AC:

AN:

41108

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

4992

South Asian (SAS)

AF:

0.0253

AC:

120

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67680

Other (OTH)

AF:

0.000951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000433

Hom.:

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gln43_Pro44insGln in exon 1 of RBM20: This variant is not expected to have cli nical significance because it has been identified in 2.0% (133/6770) of South As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs397516593). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Uncertain:1Benign:1

Dec 20, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2014

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.128_130dupAGC variant in the RBM20 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. This in-frame duplication does not occur in any of the domains thought to be critical to protein structure/function including Proline-rich domains, Glutamine-rich domains, or in the RNA Recognition Motif (RRM). The NHLBI ESP Exome Variant Server reports c.128_130dupAGC was not observed in approximately 2000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, population data from ethnically-matched backgrounds was not available at the time of this report. With the clinical and molecular information available at this time, we cannot definitively determine if c.128_130dupAGC is a disease-causing mutation or a rare benign variant. The variant is found in DCM,DCM-CRDM panel(s). -

Dilated Cardiomyopathy, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1DD

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 03, 2017

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

PhyloP100

4.0

Mutation Taster

=88/12

polymorphism

(source)

Splicing

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