10-110821474-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The NM_001134363.3(RBM20):c.2855C>T(p.Thr952Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

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: Likely_benign. The variant received -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06350464).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.2855C>T	p.Thr952Ile	missense_variant	Exon 11 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.2690C>T	p.Thr897Ile	missense_variant	Exon 11 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.2471C>T	p.Thr824Ile	missense_variant	Exon 11 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.2471C>T	p.Thr824Ile	missense_variant	Exon 11 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.2855C>T	p.Thr952Ile	missense_variant	Exon 11 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.2855C>T	p.Thr952Ile	missense_variant	Exon 11 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000357

AC:

AN:

1399538

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

690260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31600

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:

0.0000631

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079002

Other (OTH)

AF:

0.00

AC:

AN:

58040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ExAC

AF:

0.0000390

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Thr952Ile variant in RBM20 has not been reported in individuals with cardiom yopathy or in large population studies. Threonine (Thr) at position 952 is not c onserved in mammals, suggesting a change at this position is tolerated, though a dditional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to t he protein. Additional information is needed to fully assess the clinical signif icance of the Thr952Ile variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.87

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.23

M_CAP

Benign

0.079

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.61

PhyloP100

1.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.75

REVEL

Benign

0.12

Sift

Benign

0.16

Sift4G

Benign

0.19

Vest4

0.072

MutPred

0.39

Loss of disorder (P = 0.1019);

MVP

0.23

ClinPred

0.043

GERP RS

1.8

gMVP

0.17

Mutation Taster

=87/13

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