rs75858380

Positions:

chr10-110821763-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001134363.3(RBM20):c.3144C>T(p.Ser1048=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,551,772 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 72 hom. )

Consequence

RBM20
NM_001134363.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.85

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 10-110821763-C-T is Benign according to our data. Variant chr10-110821763-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110821763-C-T is described in Lovd as [Benign]. Variant chr10-110821763-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.85 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RBM20	NM_001134363.3 linkuse as main transcript	c.3144C>T	p.Ser1048=	synonymous_variant	11/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 linkuse as main transcript	c.2979C>T	p.Ser993=	synonymous_variant	11/14		XP_016871592.1
RBM20	XM_017016104.3 linkuse as main transcript	c.2760C>T	p.Ser920=	synonymous_variant	11/14		XP_016871593.1
RBM20	XM_047425116.1 linkuse as main transcript	c.2760C>T	p.Ser920=	synonymous_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.3144C>T	p.Ser1048=	synonymous_variant	11/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2216

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.0106

GnomAD3 exomes

AF:

0.00327

AC:

513

AN:

156784

Hom.:

AF XY:

0.00241

AC XY:

200

AN XY:

83066

show subpopulations

Gnomad AFR exome

AF:

0.0540

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000494

Gnomad OTH exome

AF:

0.000907

GnomAD4 exome

AF:

0.00159

AC:

2227

AN:

1399456

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

921

AN XY:

690240

show subpopulations

Gnomad4 AFR exome

AF:

0.0582

Gnomad4 AMR exome

AF:

0.00316

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000189

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000334

Gnomad4 OTH exome

AF:

0.00367

GnomAD4 genome

AF:

0.0146

AC:

2222

AN:

152316

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1069

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0509

Gnomad4 AMR

AF:

0.00516

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00634

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	Ser1048Ser in exon 11 of RMB20: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.2% (30/702) of a FRICAN American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; rs75858380). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2019	- -

Dilated cardiomyopathy 1DD

Benign:4

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 27, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 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

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.5

DANN

Benign

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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