chr10-110644496-C-G
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001134363.3(RBM20):āc.42C>Gā(p.Ser14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000046 in 1,523,228 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 33)
Exomes š: 7.3e-7 ( 0 hom. )
Consequence
RBM20
NM_001134363.3 missense
NM_001134363.3 missense
Scores
3
3
10
Clinical Significance
Conservation
PhyloP100: 0.874
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.06262857).
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.42C>G | p.Ser14Arg | missense_variant | 1/14 | ENST00000369519.4 | |
RBM20 | XM_017016103.3 | c.26+1056C>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.42C>G | p.Ser14Arg | missense_variant | 1/14 | 1 | NM_001134363.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000852 AC: 1AN: 117436Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 64800
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GnomAD4 exome AF: 7.29e-7 AC: 1AN: 1370980Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 676228
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1DD Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 19, 2012 | p.Ser14Arg (AGC>AGG): c.42 C>G in exon 1 of the RBM20 gene (NM_001134363.1). The Ser14Arg variant in the RBM20 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser14Arg results in a semi-conservative amino acid substitution of a neutral, polar Serine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Ser14Arg is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Ser14Arg was not observed in approximately 2,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy. With the clinical and molecular information available at this time, we cannot definitively determine if Ser14Arg is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2022 | The p.S14R variant (also known as c.42C>G), located in coding exon 1 of the RBM20 gene, results from a C to G substitution at nucleotide position 42. The serine at codon 14 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Benign
T
Vest4
MutPred
Loss of glycosylation at S14 (P = 0.002);
MVP
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at