10-110781289-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001134363.3(RBM20):​c.680G>T​(p.Gly227Val) variant causes a missense change. The variant allele was found at a frequency of 0.000662 in 1,551,716 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00075 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

RBM20
NM_001134363.3 missense

Scores

9
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10

Conservation

PhyloP100: 4.68
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 -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0089737475).
BP6
Variant 10-110781289-G-T is Benign according to our data. Variant chr10-110781289-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178111.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=2}. Variant chr10-110781289-G-T is described in Lovd as [Benign]. Variant chr10-110781289-G-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000755 (115/152368) while in subpopulation SAS AF= 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBM20NM_001134363.3 linkc.680G>T p.Gly227Val missense_variant Exon 2 of 14 ENST00000369519.4 NP_001127835.2 Q5T481
RBM20XM_017016103.3 linkc.515G>T p.Gly172Val missense_variant Exon 2 of 14 XP_016871592.1
RBM20XM_017016104.3 linkc.296G>T p.Gly99Val missense_variant Exon 2 of 14 XP_016871593.1
RBM20XM_047425116.1 linkc.296G>T p.Gly99Val missense_variant Exon 2 of 14 XP_047281072.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBM20ENST00000369519.4 linkc.680G>T p.Gly227Val missense_variant Exon 2 of 14 1 NM_001134363.3 ENSP00000358532.3 Q5T481

Frequencies

GnomAD3 genomes
AF:
0.000749
AC:
114
AN:
152250
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
Gnomad ASJ
AF:
0.0112
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000367
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00142
AC:
218
AN:
153808
Hom.:
0
AF XY:
0.00160
AC XY:
131
AN XY:
81634
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00113
Gnomad ASJ exome
AF:
0.0107
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00202
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000774
Gnomad OTH exome
AF:
0.00162
GnomAD4 exome
AF:
0.000652
AC:
912
AN:
1399348
Hom.:
2
Cov.:
32
AF XY:
0.000748
AC XY:
516
AN XY:
690188
show subpopulations
Gnomad4 AFR exome
AF:
0.000348
Gnomad4 AMR exome
AF:
0.00104
Gnomad4 ASJ exome
AF:
0.00997
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00159
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000341
Gnomad4 OTH exome
AF:
0.00152
GnomAD4 genome
AF:
0.000755
AC:
115
AN:
152368
Hom.:
0
Cov.:
32
AF XY:
0.000846
AC XY:
63
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.0112
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00290
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000367
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00103
Hom.:
0
Bravo
AF:
0.000706
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00157
AC:
5
ExAC
AF:
0.00172
AC:
41
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:10
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:2Benign:2
Feb 25, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 16, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Gly227Val varia nt in RBM20 has been identified by our laboratory in one Caucasian child with HC M. This variant has also been identified in 0.2% (5/3182) of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP rs202238753). Glycine (Gly) at position 227 is not well conserved in evolu tion and one mammal (panda) carries a valine (Val) at this position, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the Gly227Val variant is uncertain, these data suggest that it i s more likely to be benign. -

Nov 13, 2013
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly227Val (G227V; c.680 G>T) in the RBM20 gene. This variant has not previously been reported in individuals with DCM. The RBM20 gene is a minor cause of DCM, with mutations reported in approximately 3% of patients. This is a conservative amino acid change, resulting in the replacement of a nonpolar glycine with a nonpolar valine. Glycine at this location is 100% conserved across 8 mammalian species. The adjacent residues are not highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.976. Nonetheless, no mutations affecting nearby residues have been reported in HGMD according to GeneDx, indiacting that this region of the protein may be tolerant of change. Furthermore, the G227V variant has been seen in at least 5 individuals from >2200 individuals in publicly available population datasets. G227V is present in 5/1591 Caucasian and 0/692 African American individuals in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/). It is also listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). There is no variation at this codon in 1000 Genomes. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:4
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

RBM20: BS1, BS2 -

Jun 24, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28255936, 30611920, 25351510) -

Dilated cardiomyopathy 1DD Uncertain:1Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiomyopathy Benign:1
Sep 16, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1
Oct 01, 2016
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Cardiovascular phenotype Benign:1
May 08, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Benign
0.15
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.64
D
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.0090
T
MetaSVM
Uncertain
0.58
D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.6
D
REVEL
Uncertain
0.44
Sift
Uncertain
0.027
D
Sift4G
Uncertain
0.011
D
Vest4
0.38
MVP
0.74
ClinPred
0.11
T
GERP RS
4.7
gMVP
0.66

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: rs202238753; hg19: chr10-112541047; API