rs540962668

chr10-110781747-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001134363.3(RBM20):c.1138C>T(p.Arg380Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,551,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R380Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.418

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20851219).
• BP6: Variant 10-110781747-C-T is Benign according to our data. Variant chr10-110781747-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470584.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1138C>T	p.Arg380Trp	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.973C>T	p.Arg325Trp	missense_variant	2/14
RBM20	XM_017016104.3	c.754C>T	p.Arg252Trp	missense_variant	2/14
RBM20	XM_047425116.1	c.754C>T	p.Arg252Trp	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1138C>T	p.Arg380Trp	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000773 AC: 12 AN: 155218 Hom.: 0 AF XY: 0.0000486 AC XY: 4 AN XY: 82274

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000183

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000214 AC: 30 AN: 1399506 Hom.: 0 Cov.: 32 AF XY: 0.0000217 AC XY: 15 AN XY: 690262

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.0000689

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74490

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000716 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The p.R380W variant (also known as c.1138C>T), located in coding exon 2 of the RBM20 gene, results from a C to T substitution at nucleotide position 1138. The arginine at codon 380 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual reported to have arrhythmogenic right ventricular cardiomyopathy; however, details were not provided (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.48	N
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.035	D
Vest4		0.21
MutPred		0.37		Loss of disorder (P = 0.0011);
MVP		0.52
ClinPred		0.084	T
GERP RS		1.9
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs540962668; hg19: chr10-112541505;