chr10-110821933-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001134363.3(RBM20):c.3314C>T(p.Pro1105Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,551,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1105P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense, splice_region

Scores

Splicing: ADA: 0.006369

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.502

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.063325286).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000263 (4/152184) while in subpopulation EAS AF = 0.000384 (2/5202). AF 95% confidence interval is 0.0000681. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.3314C>T	p.Pro1105Leu	missense_variant, splice_region_variant	Exon 11 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.3149C>T	p.Pro1050Leu	missense_variant, splice_region_variant	Exon 11 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.2930C>T	p.Pro977Leu	missense_variant, splice_region_variant	Exon 11 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.2930C>T	p.Pro977Leu	missense_variant, splice_region_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.3314C>T	p.Pro1105Leu	missense_variant, splice_region_variant	Exon 11 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.3314C>T	p.Pro1105Leu	missense_variant, splice_region_variant	Exon 11 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000575

AC:

AN:

156388

AF XY:

0.0000724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000826

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1399356

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

690184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.000392

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1078948

Other (OTH)

AF:

0.0000172

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000384

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1105 of the RBM20 protein (p.Pro1105Leu). This variant is present in population databases (no rsID available, gnomAD 0.08%). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 29029073). ClinVar contains an entry for this variant (Variation ID: 470609). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RBM20 function (PMID: 29029073). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Jun 07, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with LVNC in the published literature and at GeneDx (Sedaghat-Hamedani et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies showed that this variant had no effect on splicing (Sedaghat-Hamedani et al., 2017); This variant is associated with the following publications: (PMID: 29029073) -

Cardiovascular phenotype

Uncertain:1

Feb 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P1105L variant (also known as c.3314C>T), located in coding exon 11 of the RBM20 gene, results from a C to T substitution at nucleotide position 3314. The proline at codon 1105 is replaced by leucine, an amino acid with similar properties. This variant has been detected in a left ventricular noncompaction cardiomyopathy cohort (Sedaghat-Hamedani F et al. Eur Heart J, 2017 Dec;38:3449-3460). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.61

M_CAP

Benign

0.043

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

PhyloP100

0.50

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

REVEL

Benign

0.19

Sift

Uncertain

0.0080

Sift4G

Benign

0.17

Vest4

0.095

MutPred

0.21

Gain of helix (P = 0.0199);

MVP

0.39

ClinPred

0.18

GERP RS

-1.0

gMVP

0.15

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0064

dbscSNV1_RF

Benign

0.46

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over