rs7908490

chr10-110781126-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134363.3(RBM20):c.517C>A(p.Pro173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,551,686 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P173S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.265

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001773119).
• BP6: Variant 10-110781126-C-A is Benign according to our data. Variant chr10-110781126-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 44020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110781126-C-A is described in Lovd as [Benign]. Variant chr10-110781126-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.517C>A	p.Pro173Thr	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.352C>A	p.Pro118Thr	missense_variant	2/14
RBM20	XM_017016104.3	c.133C>A	p.Pro45Thr	missense_variant	2/14
RBM20	XM_047425116.1	c.133C>A	p.Pro45Thr	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.517C>A	p.Pro173Thr	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3399 AN: 152118 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

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: 0.000294

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00504 AC: 789 AN: 156518 Hom.: 24 AF XY: 0.00379 AC XY: 314 AN XY: 82938

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00227 AC: 3179 AN: 1399450 Hom.: 112 Cov.: 32 AF XY: 0.00195 AC XY: 1345 AN XY: 690236

Gnomad4 AFR exome AF: 0.0775

Gnomad4 AMR exome AF: 0.00538

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000215

Gnomad4 FIN exome AF: 0.0000406

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.0224 AC: 3403 AN: 152236 Hom.: 124 Cov.: 32 AF XY: 0.0210 AC XY: 1566 AN XY: 74428

Gnomad4 AFR AF: 0.0774

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00413 Hom.: 26

Bravo AF: 0.0257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0708 AC: 98

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00648 AC: 177

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2012	7.1% (98/1384) of Afr Amer chrom from ESP -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2019	Variant summary: RBM20 c.517C>A (p.Pro173Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 156518 control chromosomes in the gnomAD database, including 24 homozygotes. The observed variant frequency is approximately 202 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.517C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dilated cardiomyopathy 1DD Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 11, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2015

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	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	12
Dann	Uncertain	0.99
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.21	N
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.65	T
Vest4		0.071
MVP		0.25
ClinPred		0.0045	T
GERP RS		1.5
gMVP		0.25

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

Other links and lift over

dbSNP: rs7908490; hg19: chr10-112540884;