rs397516623

chr10-110781355-G-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.746G>T(p.Gly249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G249G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.67

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=0.19725296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.746G>T	p.Gly249Val	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.581G>T	p.Gly194Val	missense_variant	2/14
RBM20	XM_017016104.3	c.362G>T	p.Gly121Val	missense_variant	2/14
RBM20	XM_047425116.1	c.362G>T	p.Gly121Val	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.746G>T	p.Gly249Val	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399316 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690172

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 07, 2012

The Gly249Val variant in RBM20 has not been reported in the literature nor previ ously identified by our laboratory. This variant has not been identified in larg e and broad European American and African American populations by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino aci d is not well conserved in evolution with the variant amino acid being present i n other species. This suggests that this change is tolerated though this inform ation is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of this variant . -

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 06, 2023

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. ClinVar contains an entry for this variant (Variation ID: 44026). 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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 249 of the RBM20 protein (p.Gly249Val). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.026	D
Vest4		0.095
MutPred		0.16		Gain of stability (P = 0.1394);
MVP		0.54
ClinPred		0.78	D
GERP RS		4.5
gMVP		0.35

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: rs397516623; hg19: chr10-112541113;