NM_001134363.3:c.1190A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001134363.3(RBM20):c.1190A>C(p.His397Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,399,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H397Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.94

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3883236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.1190A>C	p.His397Pro	missense_variant	Exon 2 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1025A>C	p.His342Pro	missense_variant	Exon 2 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.806A>C	p.His269Pro	missense_variant	Exon 2 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.806A>C	p.His269Pro	missense_variant	Exon 2 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.1190A>C	p.His397Pro	missense_variant	Exon 2 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.1190A>C	p.His397Pro	missense_variant	Exon 2 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

154396

AF XY:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1399444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1078980

Other (OTH)

AF:

0.00

AC:

AN:

58008

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 05, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The His397Pro variant in RBM20 has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis suggest that the His397Pro variant may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. In summary, the clinical significance of the His397Pro variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.80

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.35

PhyloP100

4.9

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.24

Sift

Uncertain

0.0010

Sift4G

Benign

0.20

Vest4

0.52

MutPred

0.32

Gain of relative solvent accessibility (P = 0.0249);

MVP

0.27

ClinPred

0.89

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.79

Mutation Taster

=86/14

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over