chr10-110644496-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001134363.3(RBM20):ā€‹c.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

Scores

3
3
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.874
Variant links:
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]

Genome browser will be placed here

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
RBM20NM_001134363.3 linkuse as main transcriptc.42C>G p.Ser14Arg missense_variant 1/14 ENST00000369519.4
RBM20XM_017016103.3 linkuse as main transcriptc.26+1056C>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RBM20ENST00000369519.4 linkuse as main transcriptc.42C>G p.Ser14Arg missense_variant 1/141 NM_001134363.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.000478
GnomAD3 exomes
AF:
0.00000852
AC:
1
AN:
117436
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
64800
show subpopulations
Gnomad AFR exome
AF:
0.000330
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:
7.29e-7
AC:
1
AN:
1370980
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
676228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.0000176
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.000120
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:
0.000473
Bravo
AF:
0.0000302
ExAC
AF:
0.0000422
AC:
1

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 submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 27, 2021- -
Benign, criteria provided, single submitterclinical testingInvitaeNov 06, 2023- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 19, 2012p.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 submitterclinical testingAmbry GeneticsMar 21, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
22
DANN
Uncertain
1.0
Eigen
Benign
-0.077
Eigen_PC
Benign
-0.043
FATHMM_MKL
Benign
0.46
N
M_CAP
Pathogenic
0.99
D
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-0.32
T
MutationTaster
Benign
0.98
N
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.67
N
REVEL
Uncertain
0.30
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.15
T
Vest4
0.18
MutPred
0.17
Loss of glycosylation at S14 (P = 0.002);
MVP
0.54
ClinPred
0.36
T
GERP RS
3.3
gMVP
0.23

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs541043583; hg19: chr10-112404254; API