rs558440936

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001134363.3(RBM20):c.3666C>G(p.Phe1222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 1,306,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F1222F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.735

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15503398).

BP6

Variant 10-110835960-C-G is Benign according to our data. Variant chr10-110835960-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1733723.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RBM20	NM_001134363.3 link	c.3666C>G	p.Phe1222Leu	missense_variant	Exon 14 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 link	c.3501C>G	p.Phe1167Leu	missense_variant	Exon 14 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.3282C>G	p.Phe1094Leu	missense_variant	Exon 14 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.3282C>G	p.Phe1094Leu	missense_variant	Exon 14 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RBM20	ENST00000369519.4 link	c.3666C>G	p.Phe1222Leu	missense_variant	Exon 14 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1 link	c.3666C>G	p.Phe1222Leu	missense_variant	Exon 14 of 14			ENSP00000520684.1
RBM20	ENST00000465774.2 link	n.607C>G		non_coding_transcript_exon_variant	Exon 2 of 2	4
RBM20	ENST00000480343.2 link	n.299C>G		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000727

AC:

AN:

137466

AF XY:

0.0000137

show subpopulations

Gnomad AFR exome

AF:

0.000136

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.66e-7

AC:

AN:

1154254

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

578690

show subpopulations

African (AFR)

AF:

0.0000386

AC:

AN:

25902

American (AMR)

AF:

0.00

AC:

AN:

32554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23176

East Asian (EAS)

AF:

0.00

AC:

AN:

33918

South Asian (SAS)

AF:

0.00

AC:

AN:

72126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5204

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

862760

Other (OTH)

AF:

0.00

AC:

AN:

49702

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

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:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2090

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:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 27, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Cardiovascular phenotype

Uncertain:1

Jun 26, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F1222L variant (also known as c.3666C>G), located in coding exon 14 of the RBM20 gene, results from a C to G substitution at nucleotide position 3666. The phenylalanine at codon 1222 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD

Benign:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.029

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.26

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.45

PhyloP100

-0.73

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.0

REVEL

Benign

0.13

Sift

Benign

0.073

Sift4G

Benign

0.18

Vest4

0.27

MutPred

0.21

Gain of catalytic residue at F1222 (P = 0.0169);

MVP

0.22

ClinPred

0.064

GERP RS

1.4

gMVP

0.20

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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