10-110781289-G-T

Position:

• chr10-110781289-G-T

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.680G>T​(p.Gly227Val) variant causes a missense change. The variant allele was found at a frequency of 0.000662 in 1,551,716 control chromosomes in the GnomAD database, including 2 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 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 4.68

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=0.0089737475).
• BP6: Variant 10-110781289-G-T is Benign according to our data. Variant chr10-110781289-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178111.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=3}. Variant chr10-110781289-G-T is described in Lovd as [Benign]. Variant chr10-110781289-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000755 (115/152368) while in subpopulation SAS AF= 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.680G>T	p.Gly227Val	missense_variant	2/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.515G>T	p.Gly172Val	missense_variant	2/14		XP_016871592.1
RBM20	XM_017016104.3	c.296G>T	p.Gly99Val	missense_variant	2/14		XP_016871593.1
RBM20	XM_047425116.1	c.296G>T	p.Gly99Val	missense_variant	2/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.680G>T	p.Gly227Val	missense_variant	2/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00142 AC: 218 AN: 153808 Hom.: 0 AF XY: 0.00160 AC XY: 131 AN XY: 81634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00202

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.000652 AC: 912 AN: 1399348 Hom.: 2 Cov.: 32 AF XY: 0.000748 AC XY: 516 AN XY: 690188

Gnomad4 AFR exome AF: 0.000348

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00997

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00159

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000341

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74504

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 5

ExAC AF: 0.00172 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 16, 2014	Variant classified as Uncertain Significance - Favor Benign. The Gly227Val varia nt in RBM20 has been identified by our laboratory in one Caucasian child with HC M. This variant has also been identified in 0.2% (5/3182) of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP rs202238753). Glycine (Gly) at position 227 is not well conserved in evolu tion and one mammal (panda) carries a valine (Val) at this position, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the Gly227Val variant is uncertain, these data suggest that it i s more likely to be benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 13, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly227Val (G227V; c.680 G>T) in the RBM20 gene. This variant has not previously been reported in individuals with DCM. The RBM20 gene is a minor cause of DCM, with mutations reported in approximately 3% of patients. This is a conservative amino acid change, resulting in the replacement of a nonpolar glycine with a nonpolar valine. Glycine at this location is 100% conserved across 8 mammalian species. The adjacent residues are not highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.976. Nonetheless, no mutations affecting nearby residues have been reported in HGMD according to GeneDx, indiacting that this region of the protein may be tolerant of change. Furthermore, the G227V variant has been seen in at least 5 individuals from >2200 individuals in publicly available population datasets. G227V is present in 5/1591 Caucasian and 0/692 African American individuals in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/). It is also listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). There is no variation at this codon in 1000 Genomes. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2024	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2020	This variant is associated with the following publications: (PMID: 28255936, 30611920, 25351510) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely 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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RBM20: BS1, BS2 -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
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. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 16, 2019

- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Oct 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 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	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.64	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	0.58	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.011	D
Vest4		0.38
MVP		0.74
ClinPred		0.11	T
GERP RS		4.7
gMVP		0.66

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: rs202238753; hg19: chr10-112541047;