10-110821281-G-A

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.2662G>A(p.Asp888Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00358 in 1,551,060 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts 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. D888D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 23 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:20

Conservation

PhyloP100: 6.13

Publications

16 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=0.008311868).

BP6

Variant 10-110821281-G-A is Benign according to our data. Variant chr10-110821281-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43995.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00324 (493/152322) while in subpopulation NFE AF = 0.00362 (246/68020). AF 95% confidence interval is 0.00325. There are 2 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 493 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.2662G>A	p.Asp888Asn	missense	Exon 11 of 14	NP_001127835.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBM20	ENST00000369519.4	TSL:1 MANE Select	c.2662G>A	p.Asp888Asn	missense	Exon 11 of 14	ENSP00000358532.3
RBM20	ENST00000961386.1		c.2692G>A	p.Asp898Asn	missense	Exon 11 of 14	ENSP00000631445.1
RBM20	ENST00000718239.1		c.2662G>A	p.Asp888Asn	missense	Exon 11 of 14	ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

490

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00387

AC:

603

AN:

155726

AF XY:

0.00328

show subpopulations

Gnomad AFR exome

AF:

0.000883

Gnomad AMR exome

AF:

0.000568

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00362

AC:

5059

AN:

1398738

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

2367

AN XY:

689772

show subpopulations

African (AFR)

AF:

0.000887

AC:

AN:

31572

American (AMR)

AF:

0.000588

AC:

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.000278

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35730

South Asian (SAS)

AF:

0.00

AC:

AN:

79184

European-Finnish (FIN)

AF:

0.0199

AC:

979

AN:

49258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00357

AC:

3850

AN:

1078458

Other (OTH)

AF:

0.00300

AC:

174

AN:

57984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

242

484

726

968

1210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00324

AC:

493

AN:

152322

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41570

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0191

AC:

203

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00362

AC:

246

AN:

68020

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00287

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ExAC

AF:

0.00254

AC:

Asia WGS

AF:

0.000866

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 (9)

Dilated cardiomyopathy 1DD (5)

not provided (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy;C0018790:Cardiac arrest;na:sudden unexplained death in epilepsy (1)

Primary dilated cardiomyopathy (1)

Primary dilated cardiomyopathy;C0878544:Cardiomyopathy (1)

RBM20-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.0083

MetaSVM

Uncertain

0.47

PhyloP100

6.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Vest4

0.70

MVP

0.87

ClinPred

0.042

GERP RS

5.6

gMVP

0.13

Mutation Taster

=92/8

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