10-110644468-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001134363.3(RBM20):c.14C>T(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,514,302 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.403

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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21018481).

BP6

Variant 10-110644468-C-T is Benign according to our data. Variant chr10-110644468-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1368323.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000526 (8/152178) while in subpopulation AMR AF = 0.000262 (4/15288). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.14C>T	p.Ala5Val	missense_variant	Exon 1 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.26+1028C>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.14C>T	p.Ala5Val	missense_variant	Exon 1 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481
RBM20	ENST00000718239.1 link	c.14C>T	p.Ala5Val	missense_variant	Exon 1 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000956

GnomAD4 exome

AF:

0.00000367

AC:

AN:

1362124

Hom.:

Cov.:

AF XY:

0.00000298

AC XY:

AN XY:

671694

show subpopulations

African (AFR)

AF:

0.0000359

AC:

AN:

27876

American (AMR)

AF:

0.00

AC:

AN:

32696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24134

East Asian (EAS)

AF:

0.00

AC:

AN:

32356

South Asian (SAS)

AF:

0.00

AC:

AN:

76072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4020

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1067908

Other (OTH)

AF:

0.0000708

AC:

AN:

56534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41450

American (AMR)

AF:

0.000262

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A5V variant (also known as c.14C>T), located in coding exon 1 of the RBM20 gene, results from a C to T substitution at nucleotide position 14. The alanine at codon 5 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dilated cardiomyopathy 1DD

Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.58

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.70

PhyloP100

0.40

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.33

REVEL

Benign

0.25

Sift

Benign

0.28

Sift4G

Benign

1.0

Vest4

0.28

MutPred

0.25

Gain of catalytic residue at A5 (P = 0.0375);

MVP

0.33

ClinPred

0.20

GERP RS

2.3

PromoterAI

-0.14

Neutral

(source)

gMVP

0.28

Mutation Taster

=92/8

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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10-110644468-C-T

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