rs397516597
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_001134363.3(RBM20):c.1880+4_1880+6dup variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,550,344 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0029 ( 8 hom. )
Consequence
RBM20
NM_001134363.3 splice_region, intron
NM_001134363.3 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.92
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP6
?
Variant 10-110810464-T-TGAG is Benign according to our data. Variant chr10-110810464-T-TGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43978.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (194/152144) while in subpopulation NFE AF= 0.00235 (160/68028). AF 95% confidence interval is 0.00205. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 194 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.1880+4_1880+6dup | splice_region_variant, intron_variant | ENST00000369519.4 | |||
RBM20 | XM_017016103.3 | c.1715+4_1715+6dup | splice_region_variant, intron_variant | ||||
RBM20 | XM_017016104.3 | c.1496+4_1496+6dup | splice_region_variant, intron_variant | ||||
RBM20 | XM_047425116.1 | c.1496+4_1496+6dup | splice_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.1880+4_1880+6dup | splice_region_variant, intron_variant | 1 | NM_001134363.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00128 AC: 194AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00106 AC: 166AN: 156316Hom.: 1 AF XY: 0.00111 AC XY: 92AN XY: 82832
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GnomAD4 exome AF: 0.00286 AC: 3994AN: 1398200Hom.: 8 Cov.: 29 AF XY: 0.00280 AC XY: 1930AN XY: 689672
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2020 | The c.1880+4_1880+6dupAGG variant in RBM20 is classified as likely benign because it has been identified in 0.2% (177/75818) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2021 | Variant summary: RBM20 c.1880+4_1880+6dupAGG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 156316 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.1880+4_1880+6dupAGG has been reported in the literature in sequencing studies reporting individuals affected with sporadic or familial Dialated Cardiomyopathy (example, Haas_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=1; likely benign, n=3, benign, n=1). One submitter reports this variant as having co-occurred with another pathogenic variant that clearly explained the patient phenotype. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | RBM20: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2021 | This variant is associated with the following publications: (PMID: 25163546) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Dilated cardiomyopathy 1DD Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | RBM20 NM_001134363.2 exon 8 c.1880+4_1880+6dup: This variant has been reported in the literature in at least one individual with DCM (Haas 2015 PMID:25163546). However, this variant is also present in 0.2% (177/75818) of European alleles in the Genome Aggregation Database, including 2 homozygotes (https://gnomad.broadinstitute.org/variant/10-112570222-T-TGAG) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:43978). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant occurs in the splice region, computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Dilated Cardiomyopathy, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 22, 2019 | - - |
Primary familial hypertrophic cardiomyopathy Benign:1
Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Jul 21, 2014 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 30, 2018 | 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
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at