chr1-145925876-G-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5BP4BA1
The NM_005105.5(RBM8A):c.*6C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00938 in 1,612,672 control chromosomes in the GnomAD database, including 856 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 0.042 ( 463 hom., cov: 31)
Exomes 𝑓: 0.0060 ( 393 hom. )
Consequence
RBM8A
NM_005105.5 3_prime_UTR
NM_005105.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.748
Genes affected
RBM8A (HGNC:9905): (RNA binding motif protein 8A) This gene encodes a protein with a conserved RNA-binding motif. The protein is found predominantly in the nucleus, although it is also present in the cytoplasm. It is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns had been present, thus coupling pre- and post-mRNA splicing events. Previously, it was thought that two genes encode this protein, RBM8A and RBM8B; it is now thought that the RBM8B locus is a pseudogene. There are two alternate translation start codons with this gene, which result in two forms of the protein. An allele mutation and a low-frequency noncoding single-nucleotide polymorphism (SNP) in this gene cause thrombocytopenia-absent radius (TAR) syndrome. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP5
?
Variant 1-145925876-G-C is Pathogenic according to our data. Variant chr1-145925876-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95245.We mark this variant Likely_pathogenic, oryginal submissions are: {Benign=1, Likely_pathogenic=5, Uncertain_significance=1}.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.55).. Strength limited to SUPPORTING due to the PP5.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM8A | NM_005105.5 | c.*6C>G | 3_prime_UTR_variant | 6/6 | ENST00000583313.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM8A | ENST00000583313.7 | c.*6C>G | 3_prime_UTR_variant | 6/6 | 1 | NM_005105.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0417 AC: 6350AN: 152120Hom.: 457 Cov.: 31
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GnomAD3 exomes AF: 0.0143 AC: 3583AN: 249874Hom.: 211 AF XY: 0.0127 AC XY: 1720AN XY: 135358
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GnomAD4 exome AF: 0.00599 AC: 8751AN: 1460434Hom.: 393 Cov.: 31 AF XY: 0.00600 AC XY: 4356AN XY: 726566
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GnomAD4 genome ? AF: 0.0419 AC: 6382AN: 152238Hom.: 463 Cov.: 31 AF XY: 0.0411 AC XY: 3056AN XY: 74432
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Radial aplasia-thrombocytopenia syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2021 | The RBM8A c.6*C>G variant is a 3'UTR variant that has been reported in at least 12 individuals with TAR syndrome in trans with a pathogenic 1q21.1 or 1q21.1q21.2 deletion with at least five originating from different families (Boussion et al. 2020; Morgan et al. 2020; da Rocha et al. 2021; Galvez et al. 2021). The c.6*C>G variant, segregated with the disorder in multiple affected individuals in at least three families (Boussion et al. 2020). In vitro luciferase reporter assay shows reduced expression of the RBM8A c.6*C>G construct as compared to the wild-type protein (Boussion et al. 2020). The c.6*C>G variant is found at a frequency of 0.1483 in the African/African American subpopulation of the Genome Aggregation Database (version 2.1.1). Even though this frequency is high, it does not preclude this variant's potentially damaging effect, as hypomorphic variants along with a heterozygous loss of function are a typical mechanism of TAR syndrome (Boussion et al. 2020). Based on the collective evidence, the c.6*C>G variant is classified as a likely pathogenic hypomorphic variant for TAR syndrome. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 28, 2022 | RBM8A NM_005105.4 exon 6 (3'-UTR) c.*6C>G: This variant has been reported in the literature in the compound heterozygous state in at least 14 individuals with Thrombocytopenia with Absent Radii (TAR) syndrome, most often in trans with a recurrent 200 kb deletion (Selected publications: Boussion 2020 PMID:32227665; Gálvez 2020 PMID:33718801; Morgan 2021 PMID:33559987). This variant is present in 14.2% (5886/41376) of African/African American alleles, including 454 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-145925876-G-C?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Pathogenic (Variation ID:95245). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant occurs in the 3'-UTR of this gene and does not change the coding sequence; however, literature suggests that this variant affects transcript regulation and functions as a hypomorphic allele (Albers 2012 PMID:22366785; Boussion 2020 PMID:32227665). In summary, although this variant occurs at a high minor allele frequency, there is significant evidence supporting a disease-causing impact of this variant when in trans with a null allele (Boussion 2020 PMID:32227665). Therefore, it is classified as Likely Pathogenic, but may be best regarded as a hypomorphic allele. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant summary: RBM8A c.*6C>G is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.014 in 249874 control chromosomes, predominantly at a frequency of 0.15 within the African or African-American subpopulation in the gnomAD database, including 195 homozygotes. The observed variant frequency and the high number of homozygotes suggests that the variant is benign when found in homozygous state. On the other hand, c.*6C>G has been reported in the literature in several compound heterozygous individuals, always in trans with a null allele (particularly a 1q21.1 deletion), who were affected with Radial Aplasia-Thrombocytopenia Syndrome, and the variant has been shown to segregate with disease in related individuals from multiple different families (e.g, Boussion_2020, deRocha_2021, Galvez_2021, Morgan_2020). These data suggest that the pathogenicity of the variant is genotype-dependent, i.e. highly dependent on the variant observed in trans. A publication reported experimental evidence evaluating the effect of the variant, and demonstrated that the variant resulted in reduced expression (corresponding to ~70 of the WT levels), consistent with a hypomorphic allele (Boussion_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32227665, 33718801, 33559987, 34341987). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: two submitters classified the variant as likely pathogenic, and one submitter classified it as VUS. Based on the evidence outlined above, the variant represents a hypomorphic allele that is subject to interallelic interactions, however it causes disease when in trans with a null allele, therefore, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | RBM8A: BS1, BS2 - |
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Apr 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | Hypomorphic allele that is only associated with disease when in trans with a null RBM8A allele, most frequently the 1q21.1 deletion (Boussion et al., 2020); Published functional studies suggest reduced expression consistent with a hypomorphic allele (Boussion et al., 2020); Observed on 4749/275634 (1.7229%) alleles, including hundreds of unrelated homozygous individuals in large population cohorts, which is greater than expected for a fully penetrant monogenic disorder, with the highest frequency in individuals of African descent (gnomAD); This variant is associated with the following publications: (PMID: 32227665, 32552793, 33559987, 33718801, Poulos2023[posterabstract]) - |
RBM8A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2024 | The RBM8A c.*6C>G variant is located in the 3' untranslated region. While the c.*6C>G variant is found at a high frequency (up to ~15% in gnomAD); it appears to also be found regularly in patients with thrombocytopenia with absent radius (TAR) who harbor a 1q21.1 deletion, and functional data suggest it is a hypomorphic allele, similar to the well-established hypomorphic alleles c.-21G>A and c.67+32G>C found frequently in TAR patients (Boussion et al. 2020. PubMed ID: 32227665). We characterize this variant as likely pathogenic. Of note, we did not detect a 1q21.1 deletion or another loss of function variant in the RBM8A gene in this patient. The c.*6C>G variant in the homozygous state, in the absence of another pathogenic variant in the RBM8A gene, is less likely to contribute to disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at