rs181769913

Variant names:

• chr10-110812715-A-G
• rs181769913
• NM_001134363.3:c.2318A>G

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.2318A>G​(p.Lys773Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000624 in 1,551,762 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 5.42
• Publications: 5 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), G2P, Ambry Genetics
• 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=0.006836772).
• BP6: Variant 10-110812715-A-G is Benign according to our data. Variant chr10-110812715-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199060.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00312 (475/152326) while in subpopulation AFR AF = 0.0103 (427/41576). AF 95% confidence interval is 0.00947. There are 5 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 475 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.2318A>G	p.Lys773Arg	missense	Exon 9 of 14	NP_001127835.2	Q5T481

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.2318A>G	p.Lys773Arg	missense	Exon 9 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.2348A>G	p.Lys783Arg	missense	Exon 9 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.2318A>G	p.Lys773Arg	missense	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152208 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000747 AC: 117 AN: 156524 AF XY: 0.000627

Gnomad AFR exome AF: 0.00998

Gnomad AMR exome AF: 0.000972

Gnomad ASJ exome AF: 0.000589

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000826

Gnomad OTH exome AF: 0.000910

GnomAD4 exome AF: 0.000352 AC: 493 AN: 1399436 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 186 AN XY: 690232

African (AFR) AF: 0.00911 AC: 288 AN: 31598

American (AMR) AF: 0.00132 AC: 47 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.000834 AC: 21 AN: 25182

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

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49292

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.0000741 AC: 80 AN: 1078982

Other (OTH) AF: 0.000948 AC: 55 AN: 58010

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152326 Hom.: 5 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74482

African (AFR) AF: 0.0103 AC: 427 AN: 41576

American (AMR) AF: 0.00209 AC: 32 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00112 Hom.: 6

Bravo AF: 0.00388

ExAC AF: 0.000934 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	1	1	Dilated cardiomyopathy 1DD (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.030
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.49	N
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.71	T
PhyloP100		5.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.18
Sift	Benign	0.22	T
Sift4G	Benign	0.56	T
Vest4		0.040
MVP		0.38
ClinPred		0.024	T
GERP RS		4.9
gMVP		0.094
Mutation Taster		=92/8	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: rs181769913; hg19: chr10-112572473;