Genetic Variant RBM20:p.Pro51Pro (chr10-110644607-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001134363.3(RBM20):c.153G>T(p.Pro51Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,091,326 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 2 hom. )

Consequence

RBM20
NM_001134363.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.57

Publications

0 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 10-110644607-G-T is Benign according to our data. Variant chr10-110644607-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.57 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000803 (117/145678) while in subpopulation NFE AF = 0.000166 (11/66188). AF 95% confidence interval is 0.0000929. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 117 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.153G>T	p.Pro51Pro	synonymous	Exon 1 of 14	NP_001127835.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBM20	ENST00000369519.4	TSL:1 MANE Select	c.153G>T	p.Pro51Pro	synonymous	Exon 1 of 14	ENSP00000358532.3
RBM20	ENST00000961386.1		c.153G>T	p.Pro51Pro	synonymous	Exon 1 of 14	ENSP00000631445.1
RBM20	ENST00000718239.1		c.153G>T	p.Pro51Pro	synonymous	Exon 1 of 14	ENSP00000520684.1

Frequencies

GnomAD3 genomes

AF:

0.000804

AC:

117

AN:

145534

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:

0.0113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000166

Gnomad OTH

AF:

0.000490

GnomAD2 exomes

AF:

0.000792

AC:

AN:

111114

AF XY:

0.000680

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:

0.00904

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.000301

GnomAD4 exome

AF:

0.000495

AC:

468

AN:

945648

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

208

AN XY:

475128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19772

American (AMR)

AF:

0.00

AC:

AN:

28474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17522

East Asian (EAS)

AF:

0.00

AC:

AN:

22496

South Asian (SAS)

AF:

0.00

AC:

AN:

69170

European-Finnish (FIN)

AF:

0.0125

AC:

342

AN:

27374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3068

European-Non Finnish (NFE)

AF:

0.000153

AC:

110

AN:

719406

Other (OTH)

AF:

0.000417

AC:

AN:

38366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000803

AC:

117

AN:

145678

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

71062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40332

American (AMR)

AF:

0.00

AC:

AN:

14764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

4436

South Asian (SAS)

AF:

0.00

AC:

AN:

4094

European-Finnish (FIN)

AF:

0.0113

AC:

105

AN:

9260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000166

AC:

AN:

66188

Other (OTH)

AF:

0.000485

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000549

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1DD (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

6.1

(source)

DANN

Benign

0.92

PhyloP100

1.6

PromoterAI

-0.0044

Neutral

(source)

Mutation Taster

=100/0

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