rs730880182

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001134363.3(RBM20):c.2014G>A(p.Gly672Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000135 in 1,551,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 4.94

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18816966).

BP6

Variant 10-110812411-G-A is Benign according to our data. Variant chr10-110812411-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180478.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr10-110812411-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000145 (22/152180) while in subpopulation NFE AF= 0.000309 (21/68028). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.2014G>A	p.Gly672Ser	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1849G>A	p.Gly617Ser	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1630G>A	p.Gly544Ser	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1630G>A	p.Gly544Ser	missense_variant	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.2014G>A	p.Gly672Ser	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000580

AC:

AN:

155258

Hom.:

AF XY:

0.0000485

AC XY:

AN XY:

82446

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

187

AN:

1399376

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

690198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000145

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.000110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:4Benign:1

Dec 18, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RBM20 c.2014G>A; p.Gly672Ser variant (rs730880182, ClinVar Variation ID: 180478), is reported in the literature in one individuals affected with dilated cardiomyopathy, but is presented without additional evidence of causality (McGurk 2023). This variant is found in the non-Finnish European population with an allele frequency of 0.012% (9/75366 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.223). Due to limited information, the clinical significance of this variant is uncertain at this time. References: McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022 -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1DD (MIM#613172). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (22 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS in the literature and by multiple clinical diagnostic labs (PMID: 30847666; ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:2

Jul 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with cardiomyopathy, including HCM, DCM, and ARVC, in published literature; several patients harbored additional cardiogenetic variants (PMID: 25351510, 37652022, 30847666); 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: 25351510, 37652022, 30847666) -

Aug 18, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Mar 03, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.053

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.59

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.22

Sift

Benign

0.10

Sift4G

Benign

0.17

Vest4

0.13

MVP

0.36

ClinPred

0.42

GERP RS

2.9

gMVP

0.45

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