rs727505262

Variant names:

• chr10-110781799-A-C
• rs727505262
• NM_001134363.3:c.1190A>C

Variant summary

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

The NM_001134363.3(RBM20):​c.1190A>C​(p.His397Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,399,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H397Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94
• 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), 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3883236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1190A>C	p.His397Pro	missense_variant	Exon 2 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1025A>C	p.His342Pro	missense_variant	Exon 2 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.806A>C	p.His269Pro	missense_variant	Exon 2 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.806A>C	p.His269Pro	missense_variant	Exon 2 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1190A>C	p.His397Pro	missense_variant	Exon 2 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.1190A>C	p.His397Pro	missense_variant	Exon 2 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 154396 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399444 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690228

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078980

Other (OTH) AF: 0.00 AC: 0 AN: 58008

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 05, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The His397Pro variant in RBM20 has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis suggest that the His397Pro variant may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. In summary, the clinical significance of the His397Pro variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.35	T
PhyloP100		4.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.20	T
Vest4		0.52
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0249);
MVP		0.27
ClinPred		0.89	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.79
Mutation Taster		=86/14	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: rs727505262; hg19: chr10-112541557;