rs777768807

Positions:

chr10-110835889-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001134363.3(RBM20):c.3595G>A(p.Glu1199Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,549,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict 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. E1199D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.45

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09779903).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RBM20	NM_001134363.3 linkuse as main transcript	c.3595G>A	p.Glu1199Lys	missense_variant	14/14	ENST00000369519.4
RBM20	XM_017016103.3 linkuse as main transcript	c.3430G>A	p.Glu1144Lys	missense_variant	14/14
RBM20	XM_017016104.3 linkuse as main transcript	c.3211G>A	p.Glu1071Lys	missense_variant	14/14
RBM20	XM_047425116.1 linkuse as main transcript	c.3211G>A	p.Glu1071Lys	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RBM20	ENST00000369519.4 linkuse as main transcript	c.3595G>A	p.Glu1199Lys	missense_variant	14/14	1	NM_001134363.3	P1
RBM20	ENST00000465774.2 linkuse as main transcript	n.536G>A		non_coding_transcript_exon_variant	2/2	4
RBM20	ENST00000480343.2 linkuse as main transcript	n.228G>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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

GnomAD3 exomes

AF:

0.0000265

AC:

AN:

150820

Hom.:

AF XY:

0.0000125

AC XY:

AN XY:

80250

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000441

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000265

AC:

AN:

1397786

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

689470

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.0000251

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000405

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1DD (MIM#613172). While some publications suggest a dominant negative mechanism for variants in the hotspot affecting residues between 630 and 640 (PMID: 32187365, PMID: 29895960), this has been recently disproven (PMID: 32840935). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change to an aspartic acid has been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in two individuals with HCM and another individual with SIDS (PMID: 30847666, 32789579). It has also been reported as VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2019

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 264207; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 32789579) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

The p.E1199K variant (also known as c.3595G>A), located in coding exon 14 of the RBM20 gene, results from a G to A substitution at nucleotide position 3595. The glutamic acid at codon 1199 is replaced by lysine, an amino acid with similar properties. This variant has been detected in individuals reported to have dilated cardiomyopathy, and has also been detected in a SIDS case; however, details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Köffer J et al. Int J Legal Med, 2021 Jan;135:207-212). This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in one species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence for this variant is limited at this time, its clinical significance is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.11

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.098

MetaSVM

Uncertain

-0.24

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

REVEL

Benign

0.25

Sift

Uncertain

0.015

Sift4G

Pathogenic

0.0

Vest4

0.34

MVP

0.55

ClinPred

0.096

GERP RS

3.1

gMVP

0.31

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

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