chr10-110781370-C-T

Position:

chr10-110781370-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001134363.3(RBM20):c.761C>T(p.Ser254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,551,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.00013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.46

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11154574).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000131 (20/152370) while in subpopulation AFR AF= 0.000409 (17/41588). AF 95% confidence interval is 0.00026. There are 1 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RBM20	NM_001134363.3 linkuse as main transcript	c.761C>T	p.Ser254Leu	missense_variant	2/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3 linkuse as main transcript	c.596C>T	p.Ser199Leu	missense_variant	2/14		XP_016871592.1
RBM20	XM_017016104.3 linkuse as main transcript	c.377C>T	p.Ser126Leu	missense_variant	2/14		XP_016871593.1
RBM20	XM_047425116.1 linkuse as main transcript	c.377C>T	p.Ser126Leu	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.761C>T	p.Ser254Leu	missense_variant	2/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000325

AC:

AN:

153878

Hom.:

AF XY:

0.0000367

AC XY:

AN XY:

81664

show subpopulations

Gnomad AFR exome

AF:

0.000505

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1399348

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

690186

show subpopulations

Gnomad4 AFR exome

AF:

0.000506

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.000131

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000663

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.0000424

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 25, 2022

Variant summary: RBM20 c.761C>T (p.Ser254Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 153878 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.761C>T has been reported in the literature in at least one individual without clinical information. This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrences with a pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2023

The p.S254L variant (also known as c.761C>T), located in coding exon 2 of the RBM20 gene, results from a C to T substitution at nucleotide position 761. The serine at codon 254 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.23

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.38

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Benign

0.23

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.022

Vest4

0.14

MVP

0.46

ClinPred

0.065

GERP RS

4.5

gMVP

0.20

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