rs1554886574

Positions:

• chr10-110644590-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134363.3(RBM20):​c.136C>T​(p.Pro46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,373,436 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. P46Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.85

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10969472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.136C>T	p.Pro46Ser	missense_variant	1/14	ENST00000369519.4
RBM20	XM_017016103.3	c.26+1150C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.136C>T	p.Pro46Ser	missense_variant	1/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373436 Hom.: 0 Cov.: 33 AF XY: 0.00000148 AC XY: 1 AN XY: 677384

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: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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 01, 2016

The p.Pro46Ser variant in RBM20 has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to asses s the frequency of this variant. Computational prediction tools and conservation analysis are limited for this variant. In summary, the clinical significance of the p.Pro46Ser variant is uncertain. -

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2022

This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the RBM20 protein (p.Pro46Ser). ClinVar contains an entry for this variant (Variation ID: 505314). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RBM20 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.18
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.040	D
Vest4		0.27
MutPred		0.20		Gain of phosphorylation at P46 (P = 0.0064);
MVP		0.14
ClinPred		0.21	T
GERP RS		3.6
gMVP		0.21

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: rs1554886574; hg19: chr10-112404348;