rs188054898

chr10-110821789-G-Achr10-110821789-G-T

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.3170G>A(p.Arg1057Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,551,720 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1057G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (136 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.258

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=0.0013362169).
• BP6: Variant 10-110821789-G-A is Benign according to our data. Variant chr10-110821789-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110821789-G-A is described in Lovd as [Benign]. Variant chr10-110821789-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00294 (448/152284) while in subpopulation SAS AF= 0.0522 (252/4826). AF 95% confidence interval is 0.0469. There are 11 homozygotes in gnomad4. There are 283 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 447 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.3170G>A	p.Arg1057Gln	missense_variant	11/14	ENST00000369519.4
RBM20	XM_017016103.3	c.3005G>A	p.Arg1002Gln	missense_variant	11/14
RBM20	XM_017016104.3	c.2786G>A	p.Arg929Gln	missense_variant	11/14
RBM20	XM_047425116.1	c.2786G>A	p.Arg929Gln	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.3170G>A	p.Arg1057Gln	missense_variant	11/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152166 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0268

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00928 AC: 1453 AN: 156574 Hom.: 41 AF XY: 0.0118 AC XY: 982 AN XY: 82984

Gnomad AFR exome AF: 0.000630

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0300

Gnomad SAS exome AF: 0.0476

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00354 AC: 4959 AN: 1399436 Hom.: 136 Cov.: 33 AF XY: 0.00480 AC XY: 3314 AN XY: 690226

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.0196

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000704

Gnomad4 OTH exome AF: 0.00615

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152284 Hom.: 11 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74474

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0267

Gnomad4 SAS AF: 0.0522

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00126 Hom.: 3

Bravo AF: 0.00178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00217 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0158 AC: 413

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 31, 2014	p.Arg1057Gln in exon 11 of RBM20: This variant is not expected to have clinical significance because it has been identified in 4.8% (381/7990) of South Asian ch romosomes by the by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs188054898). In addition, this variant is not conserved acros s species, including mammals. Of note, >10 mammals a glutamine (Gln) at this pos ition despite high nearby amino acid conservation. -
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	-	- -

Dilated cardiomyopathy 1DD Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 26, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 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	0.065
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.42
Dann	Benign	0.68
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.73	T
Vest4		0.021
ClinPred		0.00014	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.064

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: rs188054898; hg19: chr10-112581547; COSMIC: COSV65706092; COSMIC: COSV65706092;