Genetic Variant RBM20:p.Pro19Leu (chr10-110644510-C-T) – 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.56C>T(p.Pro19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,374,826 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. P19T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.355

Publications

0 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:

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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=0.24340317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.56C>T	p.Pro19Leu	missense_variant	Exon 1 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.26+1070C>T		intron_variant	Intron 1 of 13		XP_016871592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.56C>T	p.Pro19Leu	missense_variant	Exon 1 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.56C>T	p.Pro19Leu	missense_variant	Exon 1 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1374826

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28886

American (AMR)

AF:

0.00

AC:

AN:

34120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24526

East Asian (EAS)

AF:

0.00

AC:

AN:

33636

South Asian (SAS)

AF:

0.00

AC:

AN:

77314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072674

Other (OTH)

AF:

0.00

AC:

AN:

57032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.12

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.059

PhyloP100

0.35

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.027

Vest4

0.19

MutPred

0.17

Gain of relative solvent accessibility (P = 0.09);

MVP

0.60

ClinPred

0.59

GERP RS

3.7

PromoterAI

-0.069

Neutral

(source)

gMVP

0.23

Mutation Taster

=84/16

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