Genetic Variant RBM20:p.Pro638Pro (chr10-110812311-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001134363.3(RBM20):c.1914G>A(p.Pro638Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,550,238 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 74 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 84 hom. )

Consequence

RBM20
NM_001134363.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.87

Publications

3 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), G2P, Ambry Genetics
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 10-110812311-G-A is Benign according to our data. Variant chr10-110812311-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

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.1914G>A	p.Pro638Pro	synonymous	Exon 9 of 14	NP_001127835.2	Q5T481

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBM20	ENST00000369519.4	TSL:1 MANE Select	c.1914G>A	p.Pro638Pro	synonymous	Exon 9 of 14	ENSP00000358532.3	Q5T481
RBM20	ENST00000961386.1		c.1944G>A	p.Pro648Pro	synonymous	Exon 9 of 14	ENSP00000631445.1
RBM20	ENST00000718239.1		c.1914G>A	p.Pro638Pro	synonymous	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2514

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00372

AC:

573

AN:

153858

AF XY:

0.00274

show subpopulations

Gnomad AFR exome

AF:

0.0635

Gnomad AMR exome

AF:

0.00329

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000611

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.000920

GnomAD4 exome

AF:

0.00182

AC:

2540

AN:

1397990

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1042

AN XY:

689344

show subpopulations

African (AFR)

AF:

0.0660

AC:

2085

AN:

31576

American (AMR)

AF:

0.00348

AC:

124

AN:

35658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35704

South Asian (SAS)

AF:

0.000215

AC:

AN:

79194

European-Finnish (FIN)

AF:

0.0000411

AC:

AN:

48708

Middle Eastern (MID)

AF:

0.00246

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000464

AC:

AN:

1078330

Other (OTH)

AF:

0.00424

AC:

246

AN:

57960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

138

276

415

553

691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0166

AC:

2521

AN:

152248

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1213

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0577

AC:

2397

AN:

41540

American (AMR)

AF:

0.00575

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68004

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00562

Hom.:

Bravo

AF:

0.0187

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Dilated cardiomyopathy 1DD (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.017

(source)

DANN

Benign

0.51

PhyloP100

-3.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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