chr10-110780972-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001134363.3(RBM20):ā€‹c.363C>Gā€‹(p.Asn121Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Synonymous variant affecting the same amino acid position (i.e. N121N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

6
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.412
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RBM20NM_001134363.3 linkuse as main transcriptc.363C>G p.Asn121Lys missense_variant 2/14 ENST00000369519.4 NP_001127835.2
RBM20XM_017016103.3 linkuse as main transcriptc.198C>G p.Asn66Lys missense_variant 2/14 XP_016871592.1
RBM20XM_017016104.3 linkuse as main transcriptc.-22C>G 5_prime_UTR_variant 2/14 XP_016871593.1
RBM20XM_047425116.1 linkuse as main transcriptc.-22C>G 5_prime_UTR_variant 2/14 XP_047281072.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RBM20ENST00000369519.4 linkuse as main transcriptc.363C>G p.Asn121Lys missense_variant 2/141 NM_001134363.3 ENSP00000358532 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000143
AC:
2
AN:
1399448
Hom.:
0
Cov.:
32
AF XY:
0.00000290
AC XY:
2
AN XY:
690226
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:
9.27e-7
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2023In 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RBM20 protein function. This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 121 of the RBM20 protein (p.Asn121Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
22
DANN
Uncertain
1.0
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.83
D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Pathogenic
0.95
D
MutationTaster
Benign
0.99
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.046
D
Vest4
0.92
MutPred
0.54
Loss of helix (P = 0.0033);
MVP
0.84
ClinPred
0.99
D
GERP RS
5.0
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs727504930; hg19: chr10-112540730; API