rs542297252

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001134363.3(RBM20):​c.3517G>A​(p.Glu1173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,551,588 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

5
9
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 9.60
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 Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000263 (4/152258) while in subpopulation SAS AF= 0.00083 (4/4820). AF 95% confidence interval is 0.000283. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RBM20NM_001134363.3 linkuse as main transcriptc.3517G>A p.Glu1173Lys missense_variant 13/14 ENST00000369519.4 NP_001127835.2 Q5T481
RBM20XM_017016103.3 linkuse as main transcriptc.3352G>A p.Glu1118Lys missense_variant 13/14 XP_016871592.1
RBM20XM_017016104.3 linkuse as main transcriptc.3133G>A p.Glu1045Lys missense_variant 13/14 XP_016871593.1
RBM20XM_047425116.1 linkuse as main transcriptc.3133G>A p.Glu1045Lys missense_variant 13/14 XP_047281072.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RBM20ENST00000369519.4 linkuse as main transcriptc.3517G>A p.Glu1173Lys missense_variant 13/141 NM_001134363.3 ENSP00000358532.3 Q5T481
RBM20ENST00000471172.1 linkuse as main transcriptn.93G>A non_coding_transcript_exon_variant 2/25
RBM20ENST00000480343.2 linkuse as main transcriptn.150G>A non_coding_transcript_exon_variant 2/34

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000260
AC:
4
AN:
153930
Hom.:
0
AF XY:
0.0000367
AC XY:
3
AN XY:
81672
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000176
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000214
AC:
30
AN:
1399330
Hom.:
1
Cov.:
30
AF XY:
0.0000304
AC XY:
21
AN XY:
690176
show subpopulations
Gnomad4 AFR exome
AF:
0.0000949
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000316
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000345
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.000129
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 06, 2022In 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. ClinVar contains an entry for this variant (Variation ID: 470612). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is present in population databases (rs542297252, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1173 of the RBM20 protein (p.Glu1173Lys). -
Uncertain significance, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Stanford MedicineApr 01, 2021The p.Glu1173Lys variant in the RBM20 gene has not been previously reported in association with disease. • This variant has been identified in 4/22,770 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Computational tools predict that p.Glu1173Lys variant is deleterious; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Glu1173Lys variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP3 -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 30, 2024- -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterresearchGenetics and Genomics Program, Sidra Medicine-- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 03, 2023The p.E1173K variant (also known as c.3517G>A), located in coding exon 13 of the RBM20 gene, results from a G to A substitution at nucleotide position 3517. The glutamic acid at codon 1173 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
Pathogenic
0.78
BayesDel_addAF
Uncertain
0.079
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
30
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.62
D
MetaSVM
Uncertain
0.28
D
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.61
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0090
D
Vest4
0.82
MutPred
0.40
Gain of ubiquitination at E1173 (P = 0.0198);
MVP
0.85
ClinPred
0.58
D
GERP RS
5.4
gMVP
0.62

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: rs542297252; hg19: chr10-112590884; API