10-110835961-G-C

Variant names:

• chr10-110835961-G-C
• rs942077
• NM_001134363.3:c.3667G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134363.3(RBM20):​c.3667G>C​(p.Glu1223Gln) variant causes a missense change. The variant allele was found at a frequency of 0.828 in 1,259,556 control chromosomes in the GnomAD database, including 437,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1223H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (44456 hom., cov: 33)
  • Exomes 𝑓: 0.84 (392666 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.12
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.3003877E-7).
• BP6: Variant 10-110835961-G-C is Benign according to our data. Variant chr10-110835961-G-C is described in ClinVar as Benign. ClinVar VariationId is 44016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.3667G>C	p.Glu1223Gln	missense	Exon 14 of 14	NP_001127835.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.3667G>C	p.Glu1223Gln	missense	Exon 14 of 14	ENSP00000358532.3
	RBM20	ENST00000718239.1		c.3667G>C	p.Glu1223Gln	missense	Exon 14 of 14	ENSP00000520684.1
	RBM20	ENST00000465774.2	TSL:4	n.608G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113647 AN: 152112 Hom.: 44459 Cov.: 33

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.925

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.772

GnomAD2 exomes AF: 0.803 AC: 110677 AN: 137800 AF XY: 0.802

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.846

Gnomad EAS exome AF: 0.801

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.839 AC: 928605 AN: 1107326 Hom.: 392666 Cov.: 14 AF XY: 0.836 AC XY: 465058 AN XY: 556506

African (AFR) AF: 0.471 AC: 11835 AN: 25136

American (AMR) AF: 0.780 AC: 25144 AN: 32256

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 19272 AN: 22794

East Asian (EAS) AF: 0.766 AC: 25646 AN: 33474

South Asian (SAS) AF: 0.718 AC: 50807 AN: 70778

European-Finnish (FIN) AF: 0.864 AC: 42192 AN: 48834

Middle Eastern (MID) AF: 0.760 AC: 3876 AN: 5102

European-Non Finnish (NFE) AF: 0.866 AC: 710994 AN: 820964

Other (OTH) AF: 0.809 AC: 38839 AN: 47988

GnomAD4 genome AF: 0.747 AC: 113681 AN: 152230 Hom.: 44456 Cov.: 33 AF XY: 0.746 AC XY: 55558 AN XY: 74426

African (AFR) AF: 0.489 AC: 20299 AN: 41502

American (AMR) AF: 0.791 AC: 12110 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2950 AN: 3472

East Asian (EAS) AF: 0.789 AC: 4080 AN: 5174

South Asian (SAS) AF: 0.719 AC: 3474 AN: 4830

European-Finnish (FIN) AF: 0.862 AC: 9136 AN: 10604

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.867 AC: 58938 AN: 68018

Other (OTH) AF: 0.769 AC: 1628 AN: 2116

Alfa AF: 0.830 Hom.: 16732

Bravo AF: 0.729

TwinsUK AF: 0.876 AC: 3249

ALSPAC AF: 0.859 AC: 3312

ESP6500AA AF: 0.496 AC: 687

ESP6500EA AF: 0.872 AC: 2776

ExAC AF: 0.741 AC: 16396

Asia WGS AF: 0.704 AC: 2450 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Dilated cardiomyopathy 1DD (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	9.3e-7	T
MetaSVM	Benign	-0.92	T
PhyloP100		4.1
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.087	T
Vest4		0.032
ClinPred		0.014	T
GERP RS		5.2
gMVP		0.30
Mutation Taster		=85/15	polymorphism (auto)

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: rs942077; hg19: chr10-112595719; COSMIC: COSV65704855; COSMIC: COSV65704855;