10-110821734-C-T

Variant names:

• chr10-110821734-C-T
• rs727503392
• NM_001134363.3:c.3115C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134363.3(RBM20):​c.3115C>T​(p.Pro1039Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,551,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1039L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 2.25
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1DD

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047629).
• BP6: Variant 10-110821734-C-T is Benign according to our data. Variant chr10-110821734-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165048.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000263 (40/152316) while in subpopulation NFE AF = 0.0005 (34/68026). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3115C>T	p.Pro1039Ser	missense_variant	Exon 11 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.2950C>T	p.Pro984Ser	missense_variant	Exon 11 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.2731C>T	p.Pro911Ser	missense_variant	Exon 11 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.2731C>T	p.Pro911Ser	missense_variant	Exon 11 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3115C>T	p.Pro1039Ser	missense_variant	Exon 11 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.3115C>T	p.Pro1039Ser	missense_variant	Exon 11 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000210 AC: 33 AN: 156848 AF XY: 0.000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.000395

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000327 AC: 458 AN: 1399454 Hom.: 0 Cov.: 33 AF XY: 0.000297 AC XY: 205 AN XY: 690232

African (AFR) AF: 0.000127 AC: 4 AN: 31598

American (AMR) AF: 0.000168 AC: 6 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.000142 AC: 7 AN: 49298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.000391 AC: 422 AN: 1078980

Other (OTH) AF: 0.000327 AC: 19 AN: 58020

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74486

African (AFR) AF: 0.0000481 AC: 2 AN: 41564

American (AMR) AF: 0.000261 AC: 4 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000766 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1DD (MIM#613172). While some publications suggest a dominant negative mechanism for variants in the hotspot affecting residues between 630 and 640 (PMID: 32187365, PMID: 29895960), this mechanism has now been proven to be unlikely (PMID: 32840935). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Pathogenic variants in this gene have been described to be 66% penetrant, with age and sex also affecting penetrance (PMID: 30871348). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of cardiomyopathy, dilated, 1DD (MIM#613172). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported multiple times, as both a VUS and likely benign. While this variant has been reported in at least five individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy or sudden unexplained death, authors do not classify this variant as disease causing or pathogenic (LOVD, ClinVar, VCGS, PMID: 27650965, PMID: 30847666, PMID: 32840935, PMID: 29650543). In one family, affected individuals were also carriers of a pathogenic variant in the TTN gene (PMID: 30871348). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Analysis of this variant in transfected cells by qRT-PCR, found it had no significant effect on the splicing of target genes and affected protein did not mislocalise. While the splicing of target gene TTN was not within control range, authors speculated this was not due to this variant and consequently classified this variant as likely benign (PMID: 32840935). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

Apr 13, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Uncertain:1

Jun 29, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1

Jun 06, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 22, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro1039Ser variant in RBM20 is classified as likely benign because it has been identified in 0.04% (40/73076) of European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org dbSNP rs727503392). Com putational prediction tools and conservation analysis suggest that the p.Pro1039 Ser variant may not impact the protein. ACMG/AMP Criteria applied: BS1_supportin g, BP4. -

not provided Benign:1

Dec 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with sudden unexplained death and cardiomyopathy (Christiansen et al., 2016; van Lint et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29650543, 27650965, 30847666, 32840935) -

Cardiovascular phenotype Benign:1

Sep 29, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Benign	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.59	T
PhyloP100		2.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.20
Sift	Benign	0.27	T
Sift4G	Benign	0.39	T
Vest4		0.053
MVP		0.35
ClinPred		0.046	T
GERP RS		5.0
gMVP		0.16
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs727503392; hg19: chr10-112581492; COSMIC: COSV65707213; COSMIC: COSV65707213;