rs77110978

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/20 in silico tools predict 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. V1111L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00020 ( 4 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -4.38

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1DD
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RBM20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].

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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.3331G>A	p.Val1111Met	missense_variant	Exon 12 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.3166G>A	p.Val1056Met	missense_variant	Exon 12 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.2947G>A	p.Val983Met	missense_variant	Exon 12 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.2947G>A	p.Val983Met	missense_variant	Exon 12 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBM20	ENST00000369519.4 link	c.3331G>A	p.Val1111Met	missense_variant	Exon 12 of 14	1	NM_001134363.3	ENSP00000358532.3	Q5T481
RBM20	ENST00000718239.1 link	c.3331G>A	p.Val1111Met	missense_variant	Exon 12 of 14			ENSP00000520684.1
RBM20	ENST00000471172.1 link	n.-94G>A		upstream_gene_variant		5

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

GnomAD2 exomes

AF:

0.0000468

AC:

AN:

149530

AF XY:

0.0000506

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 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

African (AFR)

AF:

0.0000333

AC:

AN:

30016

American (AMR)

AF:

0.0000298

AC:

AN:

33590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24436

East Asian (EAS)

AF:

0.00749

AC:

256

AN:

34192

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

1058708

Other (OTH)

AF:

0.0000534

AC:

AN:

56130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000110

AC:

AN:

136784

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

65126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35798

American (AMR)

AF:

0.0000837

AC:

AN:

11942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00278

AC:

AN:

4676

South Asian (SAS)

AF:

0.00

AC:

AN:

4332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66018

Other (OTH)

AF:

0.00

AC:

AN:

1870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000426

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 26, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Jun 12, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 16, 2017

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

0.060

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.013

(source)

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

PhyloP100

-4.4

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

Mutation Taster

=94/6

polymorphism

(source)

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

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rs77110978

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over