rs201370621

Positions:

chr10-110821281-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001134363.3(RBM20):c.2662G>A(p.Asp888Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00358 in 1,551,060 control chromosomes in the GnomAD database, including 25 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 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 23 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:20

Conservation

PhyloP100: 6.13

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008311868).

BP6

Variant 10-110821281-G-A is Benign according to our data. Variant chr10-110821281-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43995.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=8, Uncertain_significance=1}. Variant chr10-110821281-G-A is described in Lovd as [Benign]. Variant chr10-110821281-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00324 (493/152322) while in subpopulation NFE AF= 0.00362 (246/68020). AF 95% confidence interval is 0.00325. There are 2 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 493 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RBM20	NM_001134363.3 linkuse as main transcript	c.2662G>A	p.Asp888Asn	missense_variant	11/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 linkuse as main transcript	c.2497G>A	p.Asp833Asn	missense_variant	11/14		XP_016871592.1
RBM20	XM_017016104.3 linkuse as main transcript	c.2278G>A	p.Asp760Asn	missense_variant	11/14		XP_016871593.1
RBM20	XM_047425116.1 linkuse as main transcript	c.2278G>A	p.Asp760Asn	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.2662G>A	p.Asp888Asn	missense_variant	11/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

490

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00387

AC:

603

AN:

155726

Hom.:

AF XY:

0.00328

AC XY:

271

AN XY:

82570

show subpopulations

Gnomad AFR exome

AF:

0.000883

Gnomad AMR exome

AF:

0.000568

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00362

AC:

5059

AN:

1398738

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

2367

AN XY:

689772

show subpopulations

Gnomad4 AFR exome

AF:

0.000887

Gnomad4 AMR exome

AF:

0.000588

Gnomad4 ASJ exome

AF:

0.000278

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0199

Gnomad4 NFE exome

AF:

0.00357

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00324

AC:

493

AN:

152322

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0191

Gnomad4 NFE

AF:

0.00362

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00299

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ExAC

AF:

0.00254

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:20

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 04, 2015	p.Asp888Asn in exon 11 of RBM20: This variant is not expected to have clinical s ignificance because it has been identified in 2% (32/1592) of Finnish chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs201370621). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2016	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	Blueprint Genetics	Feb 17, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2021	Variant summary: RBM20 c.2662G>A (p.Asp888Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 155726 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 82.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.2662G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy, without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 07, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp888Asn (c.2662 G>A) in RBM20 (NM_001134363.1) Based on failure to segregate, presence in a general population sample, and co-occurrence of other pathogenic variants in a subset of cases, we consider this variant to be a variant of uncertain significance, likely benign. It is also possible that it plays a role as a modifer though there is insufficient data available to assess that. Variants in RBM20 are relatively newly reported with cardiomyopathy and appear to be an infrequent cause of cardiomyopathy (1.9-3.0%) so only minimal data on disease-associated variation in this gene is available. Brauch et al (2009) performed genome-wide linkage analysis in two multi-generational kindreds with DCM, with a LOD score of 3.55. Sequencing of the candidate region identified two RBM20 variants, one in each family, that segregated with disease and were absent in 480 controls. They then performed DHLPC analysis of RBM20 in a cohort of 279 DCM patients and identified 6 additional families with RBM20 variants. Hershberger's group used a candidate gene approach, sequencing select RBM20 exons in 312 DCM probands and found rare variants in 6 unrelated patients. RBM20 has been implicated in abnormal TTN splicing and RBM20 deficient mice show signs of cardiomyopathy and arrhythmias (Guo et al 2013). Based on the domains identified in RBM20 it is thought to be an RNA binding protein. The variant has been seen in at least 6 unrelated cases of DCM (not including this patient) and a case of pediatric restrictive cardiomyopathy. However in one unpublished family the variant did no co-segregate with DCM. Refaat et al (2012) reported the variant in a female with DCM and atrial fibrillation. They observed RBM20 variants in 3% of the 283 patients with non-ischemic DCM studied. Patients were recruited from the US and were participants in the Genetic Risk Assessment of Defibrillator Events (GRADE) study. Per the GeneDx report the LMM has a family with this variant and DCM where the variant failed to segregate with disease. Per the LMM's ClinVar submission (SCV000060626, last reviewed by LMM January 2013), they have seen the variant in 4 individuals with clinical features of DCM, one of whom has a likely pathogenic variant in another gene. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging while SIFT predicts it to be tolerated. In total the variant has been seen in 3 of 3034 published controls and individuals from publicly available population datasets. However, the variant is listed in dbSNP with data from the exome chip and ClinSeq (rs201370621). Population frequency data in dbSNP from ClinSeq notes that 3 of ~284 individuals were heterozygous for this variant. There is no variation at codon 888 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~2750 Caucasian and African American individuals (as of March 8th, 2013). The variant was not observed in the following published control samples: 600 (Refaat et al 2012). -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 21, 2017	- -

Dilated cardiomyopathy 1DD

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	RBM20: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 20, 2017

- -

Hypertrophic cardiomyopathy;C0018790:Cardiac arrest

Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 17, 2017

This RBM20 Asp888Asn variant has previously been reported in DCM patients (Pugh TJ, et al., 2014; Refaat MM, et al., 2012) and is present in the large Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a minor allele frequency of 0.003 (European-Finnish subpopulation frequency is 0.02) which is much higher than expected for DCM (Nouhravesh N, et al., 2016) or any other inherited heart condition. Aspartic acid (Asp) at position 888 is only moderately conserved across mammals (not conserved in distantly related species). In silico tools SIFT, MutationTaster and PolyPhen-2 predict RBM20 Asp888Asn to have a possible damaging effect. Patients identified by our laboratory with the RBM20 Asp888Asn variant had different phenotypes: 1 HCM case, 1 patient who had a resuscitated cardiac arrest event, and 1 sudden unexplained death in epilepsy (SUDEP) case. In summary, based on the frequency of this variant in ~0.3% of the general population, and in 3 unrelated cases with varying disease manifestations in our data, we do not expect this variant to cause disease in isolation. In summary, we classify this variant as "benign". -

RBM20-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 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). -

Primary dilated cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 28, 2019

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Dec 01, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2015

This alteration is classified as 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

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.0083

MetaSVM

Uncertain

0.47

MutationTaster

Benign

0.99

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Vest4

0.70

MVP

0.87

ClinPred

0.042

GERP RS

5.6

gMVP

0.13

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