Genetic Variant RBM20:p.Ser1115Tyr (chr10-110823507-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001134363.3(RBM20):c.3344C>A(p.Ser1115Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000149 in 1,343,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1115F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23007289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.3344C>A	p.Ser1115Tyr	missense_variant	Exon 12 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.3179C>A	p.Ser1060Tyr	missense_variant	Exon 12 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.2960C>A	p.Ser987Tyr	missense_variant	Exon 12 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.2960C>A	p.Ser987Tyr	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.3344C>A	p.Ser1115Tyr	missense_variant	Exon 12 of 14	1	NM_001134363.3	ENSP00000358532.3	Q5T481
RBM20	ENST00000718239.1 link	c.3344C>A	p.Ser1115Tyr	missense_variant	Exon 12 of 14			ENSP00000520684.1
RBM20	ENST00000471172.1 link	n.-81C>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

153270

AF XY:

0.0000123

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 FIN exome

AF:

0.0000597

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1343450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

661488

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28676

American (AMR)

AF:

0.00

AC:

AN:

33158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23592

East Asian (EAS)

AF:

0.00

AC:

AN:

31610

South Asian (SAS)

AF:

0.00

AC:

AN:

77624

European-Finnish (FIN)

AF:

0.0000222

AC:

AN:

45040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5270

European-Non Finnish (NFE)

AF:

9.58e-7

AC:

AN:

1044288

Other (OTH)

AF:

0.00

AC:

AN:

54192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000421

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.00081

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.78

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.070

PhyloP100

5.4

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Vest4

0.26

MutPred

0.35

Gain of sheet (P = 0.0125);

MVP

0.76

ClinPred

0.80

GERP RS

6.2

gMVP

0.39

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over