rs758718732

Positions:

Variant summary

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

The NM_001134363.3(RBM20):c.785C>G(p.Thr262Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,551,690 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.17

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 (MetaRNN=0.013487756).

BP6

Variant 10-110781394-C-G is Benign according to our data. Variant chr10-110781394-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382322.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr10-110781394-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000459 (7/152362) while in subpopulation SAS AF= 0.00145 (7/4830). AF 95% confidence interval is 0.000679. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3 linkuse as main transcript	c.785C>G	p.Thr262Ser	missense_variant	2/14	ENST00000369519.4	NP_001127835.2	Q5T481
RBM20	XM_017016103.3 linkuse as main transcript	c.620C>G	p.Thr207Ser	missense_variant	2/14		XP_016871592.1
RBM20	XM_017016104.3 linkuse as main transcript	c.401C>G	p.Thr134Ser	missense_variant	2/14		XP_016871593.1
RBM20	XM_047425116.1 linkuse as main transcript	c.401C>G	p.Thr134Ser	missense_variant	2/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4 linkuse as main transcript	c.785C>G	p.Thr262Ser	missense_variant	2/14	1	NM_001134363.3	ENSP00000358532.3		Q5T481

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152244

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:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000305

AC:

AN:

153862

Hom.:

AF XY:

0.000478

AC XY:

AN XY:

81644

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 SAS exome

AF:

0.00202

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000131

AC:

184

AN:

1399328

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

130

AN XY:

690170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00216

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000278

Gnomad4 OTH exome

AF:

0.000138

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000809

AC:

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.77

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.28

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.59

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.60

REVEL

Benign

0.22

Sift

Benign

0.17

Sift4G

Benign

0.58

Vest4

0.054

MutPred

0.052

Gain of glycosylation at T262 (P = 0.0679);

MVP

0.38

ClinPred

0.019

GERP RS

3.4

gMVP

0.13

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

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