rs74339620

chr10-110812311-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001134363.3(RBM20):c.1914G>A(p.Pro638=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,550,238 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (84 hom.)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.87

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-110812311-G-A is Benign according to our data. Variant chr10-110812311-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110812311-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1914G>A	p.Pro638=	synonymous_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1749G>A	p.Pro583=	synonymous_variant	9/14
RBM20	XM_017016104.3	c.1530G>A	p.Pro510=	synonymous_variant	9/14
RBM20	XM_047425116.1	c.1530G>A	p.Pro510=	synonymous_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1914G>A	p.Pro638=	synonymous_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2514 AN: 152130 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00372 AC: 573 AN: 153858 Hom.: 14 AF XY: 0.00274 AC XY: 224 AN XY: 81854

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000441

Gnomad FIN exome AF: 0.0000611

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000920

GnomAD4 exome AF: 0.00182 AC: 2540 AN: 1397990 Hom.: 84 Cov.: 32 AF XY: 0.00151 AC XY: 1042 AN XY: 689344

Gnomad4 AFR exome AF: 0.0660

Gnomad4 AMR exome AF: 0.00348

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000215

Gnomad4 FIN exome AF: 0.0000411

Gnomad4 NFE exome AF: 0.0000464

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.0166 AC: 2521 AN: 152248 Hom.: 74 Cov.: 32 AF XY: 0.0163 AC XY: 1213 AN XY: 74432

Gnomad4 AFR AF: 0.0577

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00455 Hom.: 7

Bravo AF: 0.0187

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2014	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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1DD Benign:3

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 11, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 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
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.017
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74339620; hg19: chr10-112572069;