10-110812414-C-T

Variant names:

Variant summary

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

The NM_001134363.3(RBM20):c.2017C>T(p.Arg673Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000599 in 1,551,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R673Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 2.53

Publications

3 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 10-110812414-C-T is Benign according to our data. Variant chr10-110812414-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43984.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000615 (86/1399378) while in subpopulation NFE AF = 0.0000686 (74/1078978). AF 95% confidence interval is 0.0000559. There are 0 homozygotes in GnomAdExome4. There are 50 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RBM20	NM_001134363.3 link	c.2017C>T	p.Arg673Trp	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 link	c.1852C>T	p.Arg618Trp	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1633C>T	p.Arg545Trp	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1633C>T	p.Arg545Trp	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.2017C>T	p.Arg673Trp	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1 link	c.2017C>T	p.Arg673Trp	missense_variant	Exon 9 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152168

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000451

AC:

AN:

155232

AF XY:

0.0000728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000614

Gnomad NFE exome

AF:

0.0000667

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000615

AC:

AN:

1399378

Hom.:

Cov.:

AF XY:

0.0000724

AC XY:

AN XY:

690198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.0000280

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

49238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000686

AC:

AN:

1078978

Other (OTH)

AF:

0.0000690

AC:

AN:

58006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000460

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000866

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000395

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 09, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R673W variant in the RBM20 gene was reported in an individual referred for DCM genetic testing with a family history of sudden death; however, this individual also harbored a second variant of unknown significance in the RBM20 gene (R1008W) as well as a TTN intronic variant (Pugh et. al., 2014). The study did not provide other clinical or family history information. Additionally, The R673W variant was not observed in approximately 2,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R673W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein my tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Jul 11, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg673Trp v ariant in RBM20 has been identified by our laboratory in one adult with DCM. Dat a from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that t his variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. Pathogenic RBM20 variants frequently occur in e xon 9 of RBM20 (Brauch 2009, Li 2010), where this variant is located, though it is unclear why certain variants in this exon have a strong association with dise ase. In summary, while there is some suspicion for a pathogenic role, the clinic al significance of the Arg673Trp variant is uncertain. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Apr 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2017C>T (p.R673W) 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 2017, causing the arginine (R) at amino acid position 673 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD

Benign:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.89

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.13

PhyloP100

2.5

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.78

MVP

0.65

ClinPred

0.85

GERP RS

-0.98

gMVP

0.63

Mutation Taster

=64/36

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