chr10-110784856-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_001134363.3(RBM20):c.1494C>A(p.Ser498Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,550,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: -0.0490

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity RBM20_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.1163432).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000579 (81/1397880) while in subpopulation NFE AF = 0.0000752 (81/1077644). AF 95% confidence interval is 0.0000616. There are 0 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.1494C>A	p.Ser498Arg	missense_variant	Exon 5 of 14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.1329C>A	p.Ser443Arg	missense_variant	Exon 5 of 14		XP_016871592.1
RBM20	XM_017016104.3 link	c.1110C>A	p.Ser370Arg	missense_variant	Exon 5 of 14		XP_016871593.1
RBM20	XM_047425116.1 link	c.1110C>A	p.Ser370Arg	missense_variant	Exon 5 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 link	c.1494C>A	p.Ser498Arg	missense_variant	Exon 5 of 14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

153882

AF XY:

0.0000245

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000335

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000579

AC:

AN:

1397880

Hom.:

Cov.:

AF XY:

0.0000522

AC XY:

AN XY:

689522

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

31574

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35682

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25178

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

35734

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

79156

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

49270

Gnomad4 NFE exome

AF:

0.0000752

AC:

AN:

1077644

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

57950

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000146972

AN:

0.0000146972

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1DD

Uncertain:1Benign:1

Oct 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser498Arg variant in RBM20 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein. In summary, the clinical significance of the p.Ser498Arg va riant is uncertain. -

Cardiomyopathy

Uncertain:1

Oct 04, 2019

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.3

DANN

Benign

0.93

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.54

M_CAP

Benign

0.080

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.63

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

REVEL

Benign

0.19

Sift

Benign

0.039

Sift4G

Benign

0.35

Vest4

0.15

MutPred

0.23

Gain of solvent accessibility (P = 0.0766);

MVP

0.18

ClinPred

0.035

GERP RS

-2.6

gMVP

0.51

Mutation Taster

=30/70

disease causing

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