rs558440936

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001134363.3(RBM20):c.3666C>G(p.Phe1222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 1,306,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 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. F1222F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.735

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15503398).

BP6

Variant 10-110835960-C-G is Benign according to our data. Variant chr10-110835960-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1733723.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RBM20	NM_001134363.3 linkuse as main transcript	c.3666C>G	p.Phe1222Leu	missense_variant	14/14	ENST00000369519.4
RBM20	XM_017016103.3 linkuse as main transcript	c.3501C>G	p.Phe1167Leu	missense_variant	14/14
RBM20	XM_017016104.3 linkuse as main transcript	c.3282C>G	p.Phe1094Leu	missense_variant	14/14
RBM20	XM_047425116.1 linkuse as main transcript	c.3282C>G	p.Phe1094Leu	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RBM20	ENST00000369519.4 linkuse as main transcript	c.3666C>G	p.Phe1222Leu	missense_variant	14/14	1	NM_001134363.3	P1
RBM20	ENST00000465774.2 linkuse as main transcript	n.607C>G		non_coding_transcript_exon_variant	2/2	4
RBM20	ENST00000480343.2 linkuse as main transcript	n.299C>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

GnomAD3 exomes

AF:

0.00000727

AC:

AN:

137466

Hom.:

AF XY:

0.0000137

AC XY:

AN XY:

73186

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

8.66e-7

AC:

AN:

1154254

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

578690

show subpopulations

Gnomad4 AFR exome

AF:

0.0000386

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2020

The p.F1222L variant (also known as c.3666C>G), located in coding exon 14 of the RBM20 gene, results from a C to G substitution at nucleotide position 3666. The phenylalanine at codon 1222 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other 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. -

Dilated cardiomyopathy 1DD

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.29

Cadd

Benign

0.029

Dann

Uncertain

0.98

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.26

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.45

MutationTaster

Benign

0.87

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.0

REVEL

Benign

0.13

Sift

Benign

0.073

Sift4G

Benign

0.18

Vest4

0.27

MutPred

0.21

Gain of catalytic residue at F1222 (P = 0.0169);

MVP

0.22

ClinPred

0.064

GERP RS

1.4

gMVP

0.20

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