rs762069628

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001134363.3(RBM20):c.3574-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,550,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 splice_region, intron

Scores

Splicing: ADA: 0.01003

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.450

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 10-110835862-C-G is Benign according to our data. Variant chr10-110835862-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr10-110835862-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000515 (72/1398484) while in subpopulation MID AF= 0.00193 (11/5698). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3 link	c.3574-6C>G	splice_region_variant, intron_variant	Intron 13 of 13	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 link	c.3409-6C>G	splice_region_variant, intron_variant	Intron 13 of 13		XP_016871592.1
RBM20	XM_017016104.3 link	c.3190-6C>G	splice_region_variant, intron_variant	Intron 13 of 13		XP_016871593.1
RBM20	XM_047425116.1 link	c.3190-6C>G	splice_region_variant, intron_variant	Intron 13 of 13		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBM20	ENST00000369519.4 link	c.3574-6C>G	splice_region_variant, intron_variant	Intron 13 of 13	1	NM_001134363.3	ENSP00000358532.3	Q5T481
RBM20	ENST00000465774.2 link	n.515-6C>G	splice_region_variant, intron_variant	Intron 1 of 1	4
RBM20	ENST00000480343.2 link	n.207-6C>G	splice_region_variant, intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000132

AC:

AN:

151064

Hom.:

AF XY:

0.00

AC XY:

AN XY:

80358

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000515

AC:

AN:

1398484

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

689762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000561

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000491

Gnomad4 OTH exome

AF:

0.0000863

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jun 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3574-6C>G variant in RBM20 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pat hogenicity. In summary, the clinical significance of the c.3574-6C>G variant is uncertain. -

Cardiomyopathy

Uncertain:1

Jul 27, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1DD

Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.010

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.060

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