Variant rs950962230 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001134363.3(RBM20):c.2688G>T(p.Glu896Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000451 in 1,551,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.129

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=0.15484485).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3 linkuse as main transcript	c.2688G>T	p.Glu896Asp	missense_variant	11/14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 linkuse as main transcript	c.2523G>T	p.Glu841Asp	missense_variant	11/14		XP_016871592.1
RBM20	XM_017016104.3 linkuse as main transcript	c.2304G>T	p.Glu768Asp	missense_variant	11/14		XP_016871593.1
RBM20	XM_047425116.1 linkuse as main transcript	c.2304G>T	p.Glu768Asp	missense_variant	11/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 linkuse as main transcript	c.2688G>T	p.Glu896Asp	missense_variant	11/14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RBM20 protein function. ClinVar contains an entry for this variant (Variation ID: 576851). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 896 of the RBM20 protein (p.Glu896Asp). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2024

The p.E896D variant (also known as c.2688G>T), located in coding exon 11 of the RBM20 gene, results from a G to T substitution at nucleotide position 2688. The glutamic acid at codon 896 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, aspartic acid 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.54

M_CAP

Benign

0.012

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.64

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.0

REVEL

Benign

0.22

Sift

Benign

0.11

Sift4G

Benign

0.10

Vest4

0.19

MutPred

0.17

Loss of solvent accessibility (P = 0.1813);

MVP

0.36

ClinPred

0.61

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.065

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