rs876657971

chr10-110781633-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134363.3(RBM20):c.1024C>A(p.Pro342Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,549,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.390

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038062036).
• BP6: Variant 10-110781633-C-A is Benign according to our data. Variant chr10-110781633-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229182.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00001 (14/1397326) while in subpopulation AFR AF= 0.000413 (13/31514). AF 95% confidence interval is 0.000244. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1024C>A	p.Pro342Thr	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.859C>A	p.Pro287Thr	missense_variant	2/14
RBM20	XM_017016104.3	c.640C>A	p.Pro214Thr	missense_variant	2/14
RBM20	XM_047425116.1	c.640C>A	p.Pro214Thr	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1024C>A	p.Pro342Thr	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000129 AC: 2 AN: 154888 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82080

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000100 AC: 14 AN: 1397326 Hom.: 0 Cov.: 32 AF XY: 0.0000116 AC XY: 8 AN XY: 688868

Gnomad4 AFR exome AF: 0.000413

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: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74380

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

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: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	May 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	RBM20 NM_001134363.2 exon 2 p.Pro342Thr (c.1024C>A): This variant has not been reported in the literature and is present in 0.03% (5/16630) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-112541391-C-A). This variant is present in ClinVar (Variation ID:229182). This variant amino acid Threonine (Thr) is present in several species including the alpaca, bactrian camel, and shrew, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2018

A variant of uncertain significance has been identified in the RBM20 gene. The P342T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P342T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and where threonine is present as the wild type in several species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2022

The p.P342T variant (also known as c.1024C>A), located in coding exon 2 of the RBM20 gene, results from a C to A substitution at nucleotide position 1024. The proline at codon 342 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported in an adolescent female with acute heart failure who also had variants in TTN (reported as p.Arg23388Ter) and DMD (reported as p.Val218Ile) (Brown EE et al. Cardiol Young, 2019 Jul;29:917-921).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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 11, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	0.32
Dann	Benign	0.94
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Vest4		0.098
MutPred		0.25		Gain of phosphorylation at P342 (P = 0.0065);
MVP		0.11
ClinPred		0.015	T
GERP RS		-4.0
gMVP		0.30

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: rs876657971; hg19: chr10-112541391;