rs727505262

Positions:

• chr10-110781799-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 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. 11/18 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1190A>C	p.His397Pro	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1025A>C	p.His342Pro	missense_variant	2/14
RBM20	XM_017016104.3	c.806A>C	p.His269Pro	missense_variant	2/14
RBM20	XM_047425116.1	c.806A>C	p.His269Pro	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1190A>C	p.His397Pro	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 05, 2014

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505262; hg19: chr10-112541557;