rs201148126

chr10-110781459-G-Achr10-110781459-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001134363.3(RBM20):c.850G>A(p.Gly284Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00091 in 1,551,332 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G284E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 6.51

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29439023).
• BP6: Variant 10-110781459-G-A is Benign according to our data. Variant chr10-110781459-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44028.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4}. Variant chr10-110781459-G-A is described in Lovd as [Likely_benign]. Variant chr10-110781459-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00046 (70/152178) while in subpopulation NFE AF= 0.000838 (57/68026). AF 95% confidence interval is 0.000664. There are 1 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.850G>A	p.Gly284Arg	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.685G>A	p.Gly229Arg	missense_variant	2/14
RBM20	XM_017016104.3	c.466G>A	p.Gly156Arg	missense_variant	2/14
RBM20	XM_047425116.1	c.466G>A	p.Gly156Arg	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.850G>A	p.Gly284Arg	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000332 AC: 51 AN: 153600 Hom.: 0 AF XY: 0.000282 AC XY: 23 AN XY: 81524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

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: 0.000789

Gnomad OTH exome AF: 0.000462

GnomAD4 exome AF: 0.000959 AC: 1342 AN: 1399154 Hom.: 0 Cov.: 32 AF XY: 0.000894 AC XY: 617 AN XY: 690090

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.0000816

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.000655

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152178 Hom.: 1 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74344

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000799 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000372 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Reported in patients with cardiomyopathy and in one case of SIDS; however, some of these individuals harbored additional variants in cardiogenetic genes (Lopes et al., 2013; van Lint et al., 2019; Gaertner et al., 2020; Neubauer et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 32840935, 30871351, 28074886, 23396983) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 08, 2017	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2022	Variant summary: RBM20 c.850G>A (p.Gly284Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 153600 control chromosomes, predominantly at a frequency of 0.00079 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 17-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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.850G>A has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, sudden infant death syndrome and arrhythmogenic right ventricular cardiomyopathy (Lopes_2013, Neubauer_2017, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrences with pathogenic variants have been reported (MYBPC3 c.1624+4A>T; MYBPC3 c.1624G>C, p.E542Q; Lopes_2013 and Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign and eight ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 08, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Gly284Arg var iant in RBM20 has been identified by our laboratory in 1 Caucasian adult with fe atures of DCM and ARVC. It has also been identified in 0.07% (53/71906) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs201148126). Computational prediction tools and conservatio n analysis do not provide strong support for or against an impact to the protein . In summary, while the clinical significance of the p.Gly284Arg variant is unce rtain, its frequency suggests that it is more likely to be benign. ACMG/AMP Crit eria applied: BS1. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 21, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2021

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
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.44
Sift	Benign	0.14	T
Sift4G	Uncertain	0.0090	D
Vest4		0.55
MutPred		0.18		Loss of methylation at K280 (P = 0.073);
MVP		0.78
ClinPred		0.42	T
GERP RS		5.3
gMVP		0.61

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: rs201148126; hg19: chr10-112541217; COSMIC: COSV65705826;