chr10-110812383-G-A

Position:

• chr10-110812383-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001134363.3(RBM20):​c.1986G>A​(p.Pro662Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,551,602 control chromosomes in the GnomAD database, including 14 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 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (12 hom.)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -1.00

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-110812383-G-A is Benign according to our data. Variant chr10-110812383-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138900.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=6}. Variant chr10-110812383-G-A is described in Lovd as [Benign]. Variant chr10-110812383-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00221 (337/152262) while in subpopulation NFE AF= 0.00185 (126/68016). AF 95% confidence interval is 0.00159. There are 2 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 337 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1986G>A	p.Pro662Pro	synonymous_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1821G>A	p.Pro607Pro	synonymous_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1602G>A	p.Pro534Pro	synonymous_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1602G>A	p.Pro534Pro	synonymous_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1986G>A	p.Pro662Pro	synonymous_variant	9/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00288 AC: 446 AN: 154654 Hom.: 5 AF XY: 0.00271 AC XY: 223 AN XY: 82284

Gnomad AFR exome AF: 0.000531

Gnomad AMR exome AF: 0.000892

Gnomad ASJ exome AF: 0.000237

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00164 AC: 2295 AN: 1399340 Hom.: 12 Cov.: 32 AF XY: 0.00162 AC XY: 1119 AN XY: 690182

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.000437

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74450

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 22, 2015	p.Pro662Pro in exon 9 of RBM20: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (22/770) of Finnish chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org.; db SNP rs537723089). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Uncertain significance, 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, 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 provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	RBM20: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 20, 2016

- -

RBM20-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2016

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	-0.71
CADD	Benign	2.7
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs537723089; hg19: chr10-112572141;