NM_001134363.3:c.1898C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PS3PM1PP5BS2

The NM_001134363.3(RBM20):c.1898C>T(p.Pro633Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,546,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV007096057: Experimental studies have shown that this variant impairs protein function (PMID:37463913).". Synonymous variant affecting the same amino acid position (i.e. P633P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 7.57

Publications

11 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), G2P, Ambry Genetics
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 3 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV007096057: Experimental studies have shown that this variant impairs protein function (PMID: 37463913).

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_001134363.3

PP5

Variant 10-110812295-C-T is Pathogenic according to our data. Variant chr10-110812295-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572099.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.1898C>T	p.Pro633Leu	missense	Exon 9 of 14	NP_001127835.2	Q5T481

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBM20	ENST00000369519.4	TSL:1 MANE Select	c.1898C>T	p.Pro633Leu	missense	Exon 9 of 14	ENSP00000358532.3	Q5T481
RBM20	ENST00000961386.1		c.1928C>T	p.Pro643Leu	missense	Exon 9 of 14	ENSP00000631445.1
RBM20	ENST00000718239.1		c.1898C>T	p.Pro633Leu	missense	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000660

AC:

AN:

151498

AF XY:

0.0000124

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000717

AC:

AN:

1394344

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

686870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31508

American (AMR)

AF:

0.00

AC:

AN:

35538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25080

East Asian (EAS)

AF:

0.00

AC:

AN:

35612

South Asian (SAS)

AF:

0.0000380

AC:

AN:

79030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000651

AC:

AN:

1075910

Other (OTH)

AF:

0.00

AC:

AN:

57826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1DD (3)

Cardiovascular phenotype (1)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.65

MetaSVM

Pathogenic

0.80

PhyloP100

7.6

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Vest4

0.59

MVP

0.85

ClinPred

0.95

GERP RS

5.7

gMVP

0.56

Mutation Taster

=76/24

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over