rs561904103

Variant names:

• chr10-110812754-A-G
• rs561904103
• NM_001134363.3:c.2357A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001134363.3(RBM20):​c.2357A>G​(p.Asp786Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000432 in 1,551,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D786E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 8.47
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14174783).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000046 (7/152314) while in subpopulation AMR AF = 0.000196 (3/15302). AF 95% confidence interval is 0.0000528. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 7 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.2357A>G	p.Asp786Gly	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.2357A>G	p.Asp786Gly	missense	Exon 9 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.2387A>G	p.Asp796Gly	missense	Exon 9 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.2357A>G	p.Asp786Gly	missense	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000959 AC: 15 AN: 156466 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000429 AC: 60 AN: 1399434 Hom.: 0 Cov.: 32 AF XY: 0.0000522 AC XY: 36 AN XY: 690224

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.000224 AC: 8 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000408 AC: 44 AN: 1078978

Other (OTH) AF: 0.000138 AC: 8 AN: 58012

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74478

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000367 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.55	T
PhyloP100		8.5
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Vest4		0.18
MutPred		0.28		Gain of MoRF binding (P = 0.0384)
MVP		0.56
ClinPred		0.25	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.19
Mutation Taster		=78/22	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: rs561904103; hg19: chr10-112572512;