chr10-110821933-C-T
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001134363.3(RBM20):c.3314C>T(p.Pro1105Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,551,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1105P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001134363.3 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- dilated cardiomyopathy 1DDInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.3314C>T | p.Pro1105Leu | missense_variant, splice_region_variant | Exon 11 of 14 | ENST00000369519.4 | NP_001127835.2 | |
RBM20 | XM_017016103.3 | c.3149C>T | p.Pro1050Leu | missense_variant, splice_region_variant | Exon 11 of 14 | XP_016871592.1 | ||
RBM20 | XM_017016104.3 | c.2930C>T | p.Pro977Leu | missense_variant, splice_region_variant | Exon 11 of 14 | XP_016871593.1 | ||
RBM20 | XM_047425116.1 | c.2930C>T | p.Pro977Leu | missense_variant, splice_region_variant | Exon 11 of 14 | XP_047281072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.3314C>T | p.Pro1105Leu | missense_variant, splice_region_variant | Exon 11 of 14 | 1 | NM_001134363.3 | ENSP00000358532.3 | ||
RBM20 | ENST00000718239.1 | c.3314C>T | p.Pro1105Leu | missense_variant, splice_region_variant | Exon 11 of 14 | ENSP00000520684.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000575 AC: 9AN: 156388 AF XY: 0.0000724 show subpopulations
GnomAD4 exome AF: 0.0000179 AC: 25AN: 1399356Hom.: 0 Cov.: 33 AF XY: 0.0000188 AC XY: 13AN XY: 690184 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74342 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1DD Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1105 of the RBM20 protein (p.Pro1105Leu). This variant is present in population databases (no rsID available, gnomAD 0.08%). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 29029073). ClinVar contains an entry for this variant (Variation ID: 470609). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RBM20 function (PMID: 29029073). 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
Observed in individuals with LVNC in the published literature and at GeneDx (Sedaghat-Hamedani et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies showed that this variant had no effect on splicing (Sedaghat-Hamedani et al., 2017); This variant is associated with the following publications: (PMID: 29029073) -
Cardiovascular phenotype Uncertain:1
The p.P1105L variant (also known as c.3314C>T), located in coding exon 11 of the RBM20 gene, results from a C to T substitution at nucleotide position 3314. The proline at codon 1105 is replaced by leucine, an amino acid with similar properties. This variant has been detected in a left ventricular noncompaction cardiomyopathy cohort (Sedaghat-Hamedani F et al. Eur Heart J, 2017 Dec;38:3449-3460). This amino acid position is poorly 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at