rs769531546

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_001134363.3(RBM20):​c.3344C>T​(p.Ser1115Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 1,479,414 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).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• 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), 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2901992).
• BP6: Variant 10-110823507-C-T is Benign according to our data. Variant chr10-110823507-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 538030.
• BS2: High AC in GnomAd4 at 5 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.3344C>T	p.Ser1115Phe	missense	Exon 12 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.3344C>T	p.Ser1115Phe	missense	Exon 12 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.3374C>T	p.Ser1125Phe	missense	Exon 12 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.3344C>T	p.Ser1115Phe	missense	Exon 12 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.0000368 AC: 5 AN: 135964 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000758

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 153270 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 15 AN: 1343450 Hom.: 0 Cov.: 35 AF XY: 0.0000106 AC XY: 7 AN XY: 661488

African (AFR) AF: 0.0000349 AC: 1 AN: 28676

American (AMR) AF: 0.0000302 AC: 1 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: 0.00 AC: 0 AN: 45040

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

European-Non Finnish (NFE) AF: 0.0000124 AC: 13 AN: 1044288

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

GnomAD4 genome AF: 0.0000368 AC: 5 AN: 135964 Hom.: 0 Cov.: 29 AF XY: 0.0000308 AC XY: 2 AN XY: 65000

African (AFR) AF: 0.00 AC: 0 AN: 34920

American (AMR) AF: 0.00 AC: 0 AN: 12102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4540

South Asian (SAS) AF: 0.00 AC: 0 AN: 4132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000758 AC: 5 AN: 65920

Other (OTH) AF: 0.00 AC: 0 AN: 1878

Alfa AF: 0.0000301 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Dilated cardiomyopathy 1DD (2)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.070	T
PhyloP100		5.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.21
MutPred		0.37		Gain of sheet (P = 0.0125)
MVP		0.76
ClinPred		0.96	D
GERP RS		6.2
gMVP		0.39
Mutation Taster		=63/37	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;