rs61735272

chr10-110783376-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134363.3(RBM20):c.1286T>C(p.Leu429Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,551,300 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:13
• Conservation: PhyloP100: 4.99

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04264185).
• BP6: Variant 10-110783376-T-C is Benign according to our data. Variant chr10-110783376-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43969.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3, Benign=1}. Variant chr10-110783376-T-C is described in Lovd as [Benign]. Variant chr10-110783376-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00122 (186/152362) while in subpopulation NFE AF= 0.0021 (143/68032). AF 95% confidence interval is 0.00182. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1286T>C	p.Leu429Pro	missense_variant	3/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1121T>C	p.Leu374Pro	missense_variant	3/14
RBM20	XM_017016104.3	c.902T>C	p.Leu301Pro	missense_variant	3/14
RBM20	XM_047425116.1	c.902T>C	p.Leu301Pro	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1286T>C	p.Leu429Pro	missense_variant	3/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000955 AC: 151 AN: 158180 Hom.: 0 AF XY: 0.000899 AC XY: 75 AN XY: 83454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000884

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.00207 AC: 2901 AN: 1398938 Hom.: 5 Cov.: 30 AF XY: 0.00203 AC XY: 1398 AN XY: 689984

Gnomad4 AFR exome AF: 0.000317

Gnomad4 AMR exome AF: 0.000616

Gnomad4 ASJ exome AF: 0.000199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.000851

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74506

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00197 Hom.: 1

Bravo AF: 0.00130

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00409 AC: 13

ExAC AF: 0.000902 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 14, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1DD Uncertain:3 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	The p.Leu429Pro variant (rs61735272) has not been reported in the medical literature. The p.Leu429Pro variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.17% in the non-Finnish European population (identified in 122 out of 73,780 chromosomes), and is classified as likely benign by multiple labs in ClinVar (Variant ID: 43969). The leucine at codon 429 is weakly conserved considering 11 species (Alamut software v2.10.0), but computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Leu429Pro variant cannot be determined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Aug 20, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2020	Variant summary: RBM20 c.1286T>C (p.Leu429Pro) results in a non-conservative amino acid change located in the Matrin/U1-C-like C2H2-type zinc finger domain (IPR003604) of 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 0.0012 in 151016 control chromosomes, predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database (v3.1), including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 45-fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1286T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 5 calling it likely benign and 5 classifying it as VUS). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2012	Leu429Pro in exon 3 of RBM20: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (13/3182) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/rs61735272). Leu429Pro in exon 3 of RBM20 (rs617352 72; allele frequency = 0.4%, 13/3182) ** -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 23, 2017	- -

Cardiomyopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jan 10, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 12, 2016	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2018

This alteration is classified as likely 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.086
Sift	Benign	0.036	D
Sift4G	Benign	0.068	T
Vest4		0.68
MVP		0.52
ClinPred		0.11	T
GERP RS		4.4
gMVP		0.85

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: rs61735272; hg19: chr10-112543134;