rs77110978

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001134363.3(RBM20):c.3331G>A(p.Val1111Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,503,670 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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 0.00011 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00020 ( 4 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.38

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064791143).

BP6

Variant 10-110823494-G-A is Benign according to our data. Variant chr10-110823494-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411648.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00011 (15/136784) while in subpopulation EAS AF= 0.00278 (13/4676). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RBM20	NM_001134363.3 linkuse as main transcript	c.3331G>A	p.Val1111Met	missense_variant	12/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 linkuse as main transcript	c.3166G>A	p.Val1056Met	missense_variant	12/14		XP_016871592.1
RBM20	XM_017016104.3 linkuse as main transcript	c.2947G>A	p.Val983Met	missense_variant	12/14		XP_016871593.1
RBM20	XM_047425116.1 linkuse as main transcript	c.2947G>A	p.Val983Met	missense_variant	12/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 linkuse as main transcript	c.3331G>A	p.Val1111Met	missense_variant	12/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes

AF:

0.000110

AC:

AN:

136738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000838

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00277

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000468

AC:

AN:

149530

Hom.:

AF XY:

0.0000506

AC XY:

AN XY:

78990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000567

Gnomad SAS exome

AF:

0.0000485

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000195

AC:

267

AN:

1366886

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

130

AN XY:

673094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000333

Gnomad4 AMR exome

AF:

0.0000298

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00749

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000472

Gnomad4 OTH exome

AF:

0.0000534

GnomAD4 genome

AF:

0.000110

AC:

AN:

136784

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

65126

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000837

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00278

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000316

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000426

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2023

Variant summary: RBM20 c.3331G>A (p.Val1111Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 136738 control chromosomes, predominantly at a frequency of 0.0028 within the East Asian subpopulation in the gnomAD database (v.3.1). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 60-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 East Asian origin. To our knowledge, no occurrence of c.3331G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Dilated cardiomyopathy 1DD

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2017

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

0.060

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.013

DANN

Benign

0.77

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0032

M_CAP

Benign

0.012

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.17

REVEL

Benign

0.21

Sift

Benign

0.81

Sift4G

Benign

0.23

Vest4

0.058

MVP

0.15

ClinPred

0.021

GERP RS

-12

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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