10-110781289-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001134363.3(RBM20):c.680G>T(p.Gly227Val) variant causes a missense change. The variant allele was found at a frequency of 0.000662 in 1,551,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. G227E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:11

Conservation

PhyloP100: 4.68

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089737475).

BP6

Variant 10-110781289-G-T is Benign according to our data. Variant chr10-110781289-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178111.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000755 (115/152368) while in subpopulation SAS AF = 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 115 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.680G>T	p.Gly227Val	missense	Exon 2 of 14	NP_001127835.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBM20	ENST00000369519.4	TSL:1 MANE Select	c.680G>T	p.Gly227Val	missense	Exon 2 of 14	ENSP00000358532.3
RBM20	ENST00000961386.1		c.680G>T	p.Gly227Val	missense	Exon 2 of 14	ENSP00000631445.1
RBM20	ENST00000718239.1		c.680G>T	p.Gly227Val	missense	Exon 2 of 14	ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00142

AC:

218

AN:

153808

AF XY:

0.00160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000774

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.000652

AC:

912

AN:

1399348

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

516

AN XY:

690188

show subpopulations

African (AFR)

AF:

0.000348

AC:

AN:

31598

American (AMR)

AF:

0.00104

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00997

AC:

251

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00159

AC:

126

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49226

Middle Eastern (MID)

AF:

0.00544

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000341

AC:

368

AN:

1078966

Other (OTH)

AF:

0.00152

AC:

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000755

AC:

115

AN:

152368

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41592

American (AMR)

AF:

0.00157

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00290

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68030

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000976

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.00172

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Dilated cardiomyopathy 1DD (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.15

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.64

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

0.58

PhyloP100

4.7

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.44

Sift

Uncertain

0.027

Sift4G

Uncertain

0.011

Vest4

0.38

MVP

0.74

ClinPred

0.11

GERP RS

4.7

gMVP

0.66

Mutation Taster

=77/23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over