10-110812730-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001134363.3(RBM20):c.2333C>T(p.Ala778Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,551,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: -0.118

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.019890577).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000557 (78/1399414) while in subpopulation NFE AF = 0.0000686 (74/1078968). AF 95% confidence interval is 0.0000559. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RBM20	NM_001134363.3 link	c.2333C>T	p.Ala778Val	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 link	c.2168C>T	p.Ala723Val	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1949C>T	p.Ala650Val	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1949C>T	p.Ala650Val	missense_variant	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.2333C>T	p.Ala778Val	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1 link	c.2333C>T	p.Ala778Val	missense_variant	Exon 9 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000192

AC:

AN:

156468

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000496

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000557

AC:

AN:

1399414

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

690216

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000686

AC:

AN:

1078968

Other (OTH)

AF:

0.0000517

AC:

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000359

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:1Benign:1

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 16, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala778Val variant in the RBM20 gene has been previously reported in 1 heterozygous individual with HCM (Lopes et al., 2014). This variant has been identified in 3/60,504 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Ala778Val variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ala778Val variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4] -

not specified

Uncertain:1

Apr 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ala778Val variant (RBM20) has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. Additional information is nee ded to fully assess the clinical significance of this variant. -

Cardiomyopathy

Uncertain:1

Mar 02, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RBM20-related disorder

Uncertain:1

Sep 07, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RBM20 c.2333C>T variant is predicted to result in the amino acid substitution p.Ala778Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-112572488-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypertrophic cardiomyopathy

Uncertain:1

Apr 05, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

Cardiovascular phenotype

Uncertain:1

Jan 04, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2333C>T (p.A778V) alteration is located in exon 9 (coding exon 9) of the RBM20 gene. This alteration results from a C to T substitution at nucleotide position 2333, causing the alanine (A) at amino acid position 778 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.31

(source)

DANN

Benign

0.78

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.047

M_CAP

Benign

0.022

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

PhyloP100

-0.12

PrimateAI

Benign

0.29

PROVEAN

Benign

0.070

REVEL

Benign

0.068

Sift

Benign

0.56

Sift4G

Benign

0.61

Vest4

0.034

MutPred

0.13

Loss of ubiquitination at K773 (P = 0.1828);

MVP

0.055

ClinPred

0.017

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.12

Mutation Taster

=100/0

polymorphism

(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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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