rs1159249168

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001134363.3(RBM20):c.3602G>A(p.Gly1201Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00002 in 1,548,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1201S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.47

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13445902).

BP6

Variant 10-110835896-G-A is Benign according to our data. Variant chr10-110835896-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538017.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RBM20	NM_001134363.3 linkuse as main transcript	c.3602G>A	p.Gly1201Asp	missense_variant	14/14	ENST00000369519.4
RBM20	XM_017016103.3 linkuse as main transcript	c.3437G>A	p.Gly1146Asp	missense_variant	14/14
RBM20	XM_017016104.3 linkuse as main transcript	c.3218G>A	p.Gly1073Asp	missense_variant	14/14
RBM20	XM_047425116.1 linkuse as main transcript	c.3218G>A	p.Gly1073Asp	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RBM20	ENST00000369519.4 linkuse as main transcript	c.3602G>A	p.Gly1201Asp	missense_variant	14/14	1	NM_001134363.3	P1
RBM20	ENST00000465774.2 linkuse as main transcript	n.543G>A		non_coding_transcript_exon_variant	2/2	4
RBM20	ENST00000480343.2 linkuse as main transcript	n.235G>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000265

AC:

AN:

150708

Hom.:

AF XY:

0.0000250

AC XY:

AN XY:

80152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000702

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1396534

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

688904

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000260

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.3602G>A (p.G1201D) alteration is located in exon 14 (coding exon 14) of the RBM20 gene. This alteration results from a G to A substitution at nucleotide position 3602, causing the glycine (G) at amino acid position 1201 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.16

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.084

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.074

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.16

MutationTaster

Benign

0.73

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

REVEL

Benign

0.19

Sift

Benign

0.084

Sift4G

Benign

0.94

Vest4

0.080

MutPred

0.18

Gain of helix (P = 0.0425);

MVP

0.53

ClinPred

0.44

GERP RS

5.0

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