10-110644522-C-T

Variant names:

• chr10-110644522-C-T
• rs925693368
• NM_001134363.3:c.68C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134363.3(RBM20):​c.68C>T​(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,377,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.25

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=0.37470543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.68C>T	p.Ala23Val	missense_variant	Exon 1 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.26+1082C>T		intron_variant	Intron 1 of 13		XP_016871592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.68C>T	p.Ala23Val	missense_variant	Exon 1 of 14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1377490 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 679538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000291

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 430042). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the RBM20 protein (p.Ala23Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RBM20-related conditions (Invitae). 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. 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. -

not provided Uncertain:1

May 12, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A23V variant of uncertain significance in the RBM20 gene has not been published as pathogenic or been reported as benign to our knowledge. The A23V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this variant is not located in the exon 9 hot-spot" region of the RBM20 gene, where many pathogenic variants are located (Brauch et al., 2009). Nevertheless, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, data from control individuals was not available to assess whether A23V may be a common benign variant in the general population.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign." -

Cardiovascular phenotype Uncertain:1

May 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A23V variant (also known as c.68C>T), located in coding exon 1 of the RBM20 gene, results from a C to T substitution at nucleotide position 68. The alanine at codon 23 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.53	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.084	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.29	T
Vest4		0.24
MutPred		0.13		Gain of sheet (P = 0.0221);
MVP		0.85
ClinPred		0.96	D
GERP RS		4.2
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: rs925693368; hg19: chr10-112404280;