NM_001134363.3:c.2371C>T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_001134363.3(RBM20):c.2371C>T(p.Arg791Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000251 in 1,551,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.16

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36494023).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000046 (7/152242) while in subpopulation AMR AF= 0.000327 (5/15298). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.2371C>T	p.Arg791Trp	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.2206C>T	p.Arg736Trp	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1987C>T	p.Arg663Trp	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1987C>T	p.Arg663Trp	missense_variant	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.2371C>T	p.Arg791Trp	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000256

AC:

AN:

156410

Hom.:

AF XY:

0.0000362

AC XY:

AN XY:

82892

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000917

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1399390

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

690202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000213

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:1Benign:1

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Uncertain:1

Feb 12, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Dec 22, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

May 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R791W variant (also known as c.2371C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 2371. The arginine at codon 791 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Horvat C et al. Genet Med, 2019 Jan;21:133-143). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.54

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.24

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.51

MutPred

0.23

Gain of glycosylation at P796 (P = 0.1061);

MVP

0.70

ClinPred

0.98

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over