rs116908219

Positions:

• chr10-110823536-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134363.3(RBM20):​c.3373G>A​(p.Glu1125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,545,238 control chromosomes in the GnomAD database, including 20 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0038 (20 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.33

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007486701).
• BP6: Variant 10-110823536-G-A is Benign according to our data. Variant chr10-110823536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110823536-G-A is described in Lovd as [Benign]. Variant chr10-110823536-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00326 (484/148400) while in subpopulation NFE AF= 0.00457 (309/67630). AF 95% confidence interval is 0.00415. There are 0 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 484 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3373G>A	p.Glu1125Lys	missense_variant	12/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3208G>A	p.Glu1070Lys	missense_variant	12/14		XP_016871592.1
RBM20	XM_017016104.3	c.2989G>A	p.Glu997Lys	missense_variant	12/14		XP_016871593.1
RBM20	XM_047425116.1	c.2989G>A	p.Glu997Lys	missense_variant	12/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3373G>A	p.Glu1125Lys	missense_variant	12/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 484 AN: 148290 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000782

Gnomad AMI AF: 0.00664

Gnomad AMR AF: 0.00376

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000426

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00295

GnomAD3 exomes AF: 0.00362 AC: 567 AN: 156520 Hom.: 4 AF XY: 0.00354 AC XY: 294 AN XY: 82962

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000483

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00509

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00381 AC: 5325 AN: 1396838 Hom.: 20 Cov.: 35 AF XY: 0.00382 AC XY: 2630 AN XY: 688914

Gnomad4 AFR exome AF: 0.000606

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00326 AC: 484 AN: 148400 Hom.: 0 Cov.: 30 AF XY: 0.00314 AC XY: 227 AN XY: 72256

Gnomad4 AFR AF: 0.000780

Gnomad4 AMR AF: 0.00375

Gnomad4 ASJ AF: 0.0180

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000426

Gnomad4 FIN AF: 0.00121

Gnomad4 NFE AF: 0.00457

Gnomad4 OTH AF: 0.00292

Alfa AF: 0.00493 Hom.: 0

Bravo AF: 0.00323

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00534 AC: 17

ExAC AF: 0.00340 AC: 81

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2017	p.Glu1125Lys in exon 12 of RBM20: This variant is classified as benign because i t has been identified in 1.8% (157/8538) of Ashkenazi Jewish chromosomes, includ ing 4 homozygotes by the Genome Aggregation Database (gnomAD, http://gmomad.broa dinstitute.org; dbSNP rs116908219). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2020	Variant summary: RBM20 c.3373G>A (p.Glu1125Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 156520 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 145-fold the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.3373G>A has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (examples- Lopes_2013, Pugh_2014, Bottillo_2016, Jaaskelainen_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as benign (n=4), likely benign (n=4) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2018	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 18, 2016	- -

Dilated cardiomyopathy 1DD Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RBM20: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 18, 2017

- -

Long QT syndrome;C0349788:Arrhythmogenic right ventricular cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 18, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2018

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	0.092
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Benign	0.037	D
Sift4G	Benign	0.073	T
Vest4		0.29
MVP		0.71
ClinPred		0.011	T
GERP RS		6.2
gMVP		0.48

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

Other links and lift over

dbSNP: rs116908219; hg19: chr10-112583294;