10-110797518-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001134363.3(RBM20):c.1538G>A(p.Arg513Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,550,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R513W) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.67

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22621861).

BP6

Variant 10-110797518-G-A is Benign according to our data. Variant chr10-110797518-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229187.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.1538G>A	p.Arg513Gln	missense_variant	Exon 6 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1373G>A	p.Arg458Gln	missense_variant	Exon 6 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1154G>A	p.Arg385Gln	missense_variant	Exon 6 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1154G>A	p.Arg385Gln	missense_variant	Exon 6 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.1538G>A	p.Arg513Gln	missense_variant	Exon 6 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000128

AC:

AN:

156134

AF XY:

0.0000121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000407

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:

0.0000107

AC:

AN:

1398764

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

689870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

31582

Gnomad4 AMR exome

AF:

0.0000841

AC:

AN:

35686

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25158

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

35726

Gnomad4 SAS exome

AF:

0.0000126

AC:

AN:

79130

Gnomad4 FIN exome

AF:

0.0000812

AC:

AN:

49266

Gnomad4 NFE exome

AF:

0.00000649

AC:

AN:

1078636

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

57968

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000241429

AN:

0.0000241429

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.000014699

AN:

0.000014699

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg513Gln variant in RBM20 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein though one mammalian species (cape golden mole ) carries the variant amino acid at this position, raising the possibility that it may be tolerated. In summary, the clinical significance of the p.Arg513Gln va riant is uncertain. -

not provided

Uncertain:1

Sep 18, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1DD

Benign:1

Nov 30, 2023

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

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

-0.042

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.62

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.25

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.30

Sift

Uncertain

0.013

Sift4G

Uncertain

0.015

Vest4

0.14

MutPred

0.40

Gain of ubiquitination at K514 (P = 0.0317);

MVP

0.54

ClinPred

0.91

GERP RS

4.8

gMVP

0.70

Mutation Taster

=69/31

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over