rs757389650

Variant names:

• chr10-110835910-G-A
• rs757389650
• NM_001134363.3:c.3616G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110835910-G-A
• chr10-110835910-G-T

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.3616G>A​(p.Glu1206Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,540,606 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. E1206Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 5.19
• Publications: 8 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=0.22480199).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000723 (11/152232) while in subpopulation AFR AF = 0.000241 (10/41456). AF 95% confidence interval is 0.00013. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 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.3616G>A	p.Glu1206Lys	missense	Exon 14 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.3616G>A	p.Glu1206Lys	missense	Exon 14 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.3646G>A	p.Glu1216Lys	missense	Exon 14 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.3616G>A	p.Glu1206Lys	missense	Exon 14 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000467 AC: 7 AN: 149856 AF XY: 0.0000251

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000382 AC: 53 AN: 1388374 Hom.: 0 Cov.: 28 AF XY: 0.0000350 AC XY: 24 AN XY: 685420

African (AFR) AF: 0.000128 AC: 4 AN: 31292

American (AMR) AF: 0.0000844 AC: 3 AN: 35552

Ashkenazi Jewish (ASJ) AF: 0.000239 AC: 6 AN: 25104

East Asian (EAS) AF: 0.00 AC: 0 AN: 35554

South Asian (SAS) AF: 0.000101 AC: 8 AN: 78838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000271 AC: 29 AN: 1069482

Other (OTH) AF: 0.0000521 AC: 3 AN: 57632

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74372

African (AFR) AF: 0.000241 AC: 10 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000598 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000413 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Dilated cardiomyopathy 1DD (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Primary familial dilated cardiomyopathy (1)
-	1	-	RBM20-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.072	D
PhyloP100		5.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.14
MVP		0.69
ClinPred		0.15	T
GERP RS		5.0
gMVP		0.49
Mutation Taster		=36/64	disease causing

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: rs757389650; hg19: chr10-112595668; COSMIC: COSV65703217; COSMIC: COSV65703217;