rs189569984

Variant names:

• chr10-110784367-C-T
• rs189569984
• NM_001134363.3:c.1364C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001134363.3(RBM20):​c.1364C>T​(p.Ser455Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00703 in 1,551,030 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S455S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (54 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:18
• Conservation: PhyloP100: 5.08
• Publications: 18 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 -16 ACMG points.

• BP6: Variant 10-110784367-C-T is Benign according to our data. Variant chr10-110784367-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00538 (819/152264) while in subpopulation NFE AF = 0.00782 (532/68016). AF 95% confidence interval is 0.00727. There are 4 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 819 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.1364C>T	p.Ser455Leu	missense	Exon 4 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.1364C>T	p.Ser455Leu	missense	Exon 4 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.1394C>T	p.Ser465Leu	missense	Exon 4 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.1364C>T	p.Ser455Leu	missense	Exon 4 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 818 AN: 152146 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00560 AC: 862 AN: 153884 AF XY: 0.00529

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00672

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000982

Gnomad NFE exome AF: 0.00781

Gnomad OTH exome AF: 0.00923

GnomAD4 exome AF: 0.00721 AC: 10086 AN: 1398766 Hom.: 54 Cov.: 31 AF XY: 0.00702 AC XY: 4843 AN XY: 689922

African (AFR) AF: 0.00133 AC: 42 AN: 31590

American (AMR) AF: 0.00655 AC: 234 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 486 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.000530 AC: 42 AN: 79180

European-Finnish (FIN) AF: 0.000975 AC: 48 AN: 49256

Middle Eastern (MID) AF: 0.000920 AC: 5 AN: 5434

European-Non Finnish (NFE) AF: 0.00813 AC: 8766 AN: 1078736

Other (OTH) AF: 0.00797 AC: 462 AN: 57958

GnomAD4 genome AF: 0.00538 AC: 819 AN: 152264 Hom.: 4 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74438

African (AFR) AF: 0.00171 AC: 71 AN: 41542

American (AMR) AF: 0.00666 AC: 102 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00782 AC: 532 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00719 Hom.: 15

Bravo AF: 0.00562

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.0104 AC: 33

ExAC AF: 0.00422 AC: 98

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	Dilated cardiomyopathy 1DD (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.64	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.42	T
PhyloP100		5.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Vest4		0.43
MVP		0.57
ClinPred		0.039	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.58
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs189569984; hg19: chr10-112544125; COSMIC: COSV99055419;