NM_001134363.3:c.28G>A

Variant names:

• chr10-110644482-G-A
• NM_001134363.3:c.28G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134363.3(RBM20):​c.28G>A​(p.Asp10Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,368,676 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29422742).

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.28G>A	p.Asp10Asn	missense	Exon 1 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.28G>A	p.Asp10Asn	missense	Exon 1 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.28G>A	p.Asp10Asn	missense	Exon 1 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.28G>A	p.Asp10Asn	missense	Exon 1 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1368676 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 675116

African (AFR) AF: 0.00 AC: 0 AN: 28298

American (AMR) AF: 0.00 AC: 0 AN: 33500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24340

East Asian (EAS) AF: 0.00 AC: 0 AN: 32964

South Asian (SAS) AF: 0.00 AC: 0 AN: 76718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070518

Other (OTH) AF: 0.00 AC: 0 AN: 56790

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.70	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.34	T
PhyloP100		2.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.39	T
Vest4		0.22
MutPred		0.18		Gain of relative solvent accessibility (P = 0.09)
MVP		0.55
ClinPred		0.95	D
GERP RS		4.2
PromoterAI		0.019	Neutral
gMVP		0.11
Mutation Taster		=84/16	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

hg19: chr10-112404240;