rs769531546

Variant names:

• chr10-110823507-C-A
• rs769531546
• NM_001134363.3:c.3344C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110823507-C-A
• chr10-110823507-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134363.3(RBM20):​c.3344C>A​(p.Ser1115Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000149 in 1,343,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1115F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23007289).

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.3344C>A	p.Ser1115Tyr	missense	Exon 12 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.3344C>A	p.Ser1115Tyr	missense	Exon 12 of 14	ENSP00000358532.3
	RBM20	ENST00000718239.1		c.3344C>A	p.Ser1115Tyr	missense	Exon 12 of 14	ENSP00000520684.1
	RBM20	ENST00000471172.1	TSL:5	n.-81C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 153270 AF XY: 0.0000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000597

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1343450 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 661488

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28676

American (AMR) AF: 0.00 AC: 0 AN: 33158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23592

East Asian (EAS) AF: 0.00 AC: 0 AN: 31610

South Asian (SAS) AF: 0.00 AC: 0 AN: 77624

European-Finnish (FIN) AF: 0.0000222 AC: 1 AN: 45040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5270

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1044288

Other (OTH) AF: 0.00 AC: 0 AN: 54192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ExAC AF: 0.0000421 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.00081	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.070	T
PhyloP100		5.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.26
MutPred		0.35		Gain of sheet (P = 0.0125)
MVP		0.76
ClinPred		0.80	D
GERP RS		6.2
gMVP		0.39
Mutation Taster		=62/38	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: rs769531546; hg19: chr10-112583265; COSMIC: COSV101051428; COSMIC: COSV101051428;