rs200588338

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001134363.3(RBM20):c.1179C>T(p.Pro393=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,551,698 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 1 hom. )

Consequence

RBM20
NM_001134363.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -0.170

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 10-110781788-C-T is Benign according to our data. Variant chr10-110781788-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43966.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=4, Uncertain_significance=1}. Variant chr10-110781788-C-T is described in Lovd as [Benign]. Variant chr10-110781788-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.17 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000742 (113/152242) while in subpopulation NFE AF= 0.00128 (87/68044). AF 95% confidence interval is 0.00106. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RBM20	NM_001134363.3 linkuse as main transcript	c.1179C>T	p.Pro393=	synonymous_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3 linkuse as main transcript	c.1014C>T	p.Pro338=	synonymous_variant	2/14
RBM20	XM_017016104.3 linkuse as main transcript	c.795C>T	p.Pro265=	synonymous_variant	2/14
RBM20	XM_047425116.1 linkuse as main transcript	c.795C>T	p.Pro265=	synonymous_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4 linkuse as main transcript	c.1179C>T	p.Pro393=	synonymous_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000742

AC:

113

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000699

AC:

108

AN:

154474

Hom.:

AF XY:

0.000731

AC XY:

AN XY:

82042

show subpopulations

Gnomad AFR exome

AF:

0.000252

Gnomad AMR exome

AF:

0.000162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000483

Gnomad FIN exome

AF:

0.000119

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00145

AC:

2035

AN:

1399456

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1018

AN XY:

690234

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000543

Gnomad4 FIN exome

AF:

0.0000406

Gnomad4 NFE exome

AF:

0.00175

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152242

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000740

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 30, 2013	Pro393Pro in exon 2 of RBM20: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. Pro393Pro in exon 2 of RBM20 (allele frequen cy = n/a) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	RBM20: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dilated cardiomyopathy 1DD

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 07, 2018

- -

RBM20-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

Cadd

Benign

6.4

Dann

Benign

0.68

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