rs201779890
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting
The NM_005105.5(RBM8A):c.67+32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,603,802 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic low penetrance (★★).
Frequency
Consequence
NM_005105.5 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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RBM8A | NM_005105.5 | c.67+32G>C | intron_variant | Intron 1 of 5 | ENST00000583313.7 | NP_005096.1 | ||
LIX1L-AS1 | NR_147182.1 | n.381C>G | non_coding_transcript_exon_variant | Exon 2 of 3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM8A | ENST00000583313.7 | c.67+32G>C | intron_variant | Intron 1 of 5 | 1 | NM_005105.5 | ENSP00000463058.2 | |||
ENSG00000280778 | ENST00000625258.1 | c.-30+39C>G | intron_variant | Intron 1 of 3 | 5 | ENSP00000487094.1 |
Frequencies
GnomAD3 genomes AF: 0.00489 AC: 744AN: 152140Hom.: 5 Cov.: 31
GnomAD3 exomes AF: 0.00547 AC: 1281AN: 234162Hom.: 8 AF XY: 0.00545 AC XY: 688AN XY: 126236
GnomAD4 exome AF: 0.00482 AC: 6994AN: 1451544Hom.: 47 Cov.: 31 AF XY: 0.00475 AC XY: 3422AN XY: 720966
GnomAD4 genome AF: 0.00489 AC: 744AN: 152258Hom.: 5 Cov.: 31 AF XY: 0.00533 AC XY: 397AN XY: 74438
ClinVar
Submissions by phenotype
Radial aplasia-thrombocytopenia syndrome Pathogenic:8Other:1
Variant summary: RBM8A c.67+32G>C is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 0.0055 in 234162 control chromosomes in the gnomAD database, including 8 homozygotes. Homozygotes in this variant are not expected to have features of TAR due to compound inheritance mechanism of this disease. c.67+32G>C has been reported to segregate with disease in the literature in multiple individuals affected with Radial Aplasia-Thrombocytopenia Syndrome, combined with a 1q21.1 deletion (Albers_2012). These data indicate that the variant is very likely to be associated with disease. Experimental studies suggest a reduced expression of the RBM8A protein and possibly disrupting a transcription factor binding site (Albers_2012). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=8) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
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NG_032654.2(NM_005105.4):c.67+32G>C in the RBM8A gene has an allele frequency of 0.023 in European(non-Finnish) subpopulation in the gnomAD database. Experimental studies have reported that c.67+32G>C leads to a partial decrease in RBM8A expression in vitro, possibly by disrupting a transcription factor binding site (PMID: 22366785). It was detected in multiple individuals with Radial aplasia-thrombocytopenia syndrome, compound heterozygous with a submicroscopic deletion encompassing the RBM8A gene (PMID: 22366785). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4. -
This variant was identified as hemizygous in trans with a 414kb Deletion causative for the TAR Syndrome._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 -
The c.67+32G>C variant in RBM8A has been reported in >25 individuals with thromb ocytopenia with absent radius (TAR) syndrome, all of whom had a submicroscopic d eletion encompassing the RBM8A gene on the second allele (Albers 2012, Manukjan 2017), suggesting that compound heterozygosity for this variant and a loss of fu nction variant in RBM8A is disease causing. In vitro studies demonstrated that t his variant may lead to reduced gene expression (Albers 2012). Although this var iant has also been identified in 2.5% (562/24044) of Finnish and 0.7% (883/11850 8) of other European chromosomes, including 11 homozygotes, by the Genome Aggreg ation Database (gnomAD, http://exac.broadinstitute.org; dbSNP rs201779890), loss of function variants in RBM8A are very rare in large population studies, sugges ting that compound heterozygosity for the c.67+32G>C variant and a loss of funct ion variant in RBM8A is rare. Compound heterozygosity for this variant and a los s-of-function variant in RBM8A is strongly associated with TAR syndrome. Note th at individuals that are homozygous for this variant are not expected to have fea tures of TAR syndrome. In summary, this variant is pathogenic for TAR syndrome i n an autosomal recessive manner. ACMG/AMP Criteria applied: PS3, PM3_VeryStrong. -
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This sequence change falls in intron 1 of the RBM8A gene. It does not directly change the encoded amino acid sequence of the RBM8A protein. Experimental studies have reported that this variant leads to a partial decrease in RBM8A expression in vitro, possibly by disrupting a transcription factor binding site (PMID: 22366785). This variant is present in population databases (rs201779890, gnomAD 2.3%), including at least one homozygous and/or hemizygous individual. This variant has been observed on the opposite chromosome (in trans) from a whole gene deletion of RBM8A in several individuals affected with TAR syndrome (PMID: 22366785). However, it has been reported as homozygous in an unaffected parent (PMID: 22366785). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the RBM8A gene, it has been classified as Pathogenic (low penetrance). -
not provided Pathogenic:7
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Observed multiple times with a null pathogenic variant on the opposite allele (in trans) in unrelated patients with TAR syndrome in the published literature (PMID: 22366785, 28857120); Published functional studies suggest a damaging effect due to disruption of a transcription factor binding site and reduced expression of the resulting protein, consistent with a hypomorphic allele (PMID: 22366785); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30609409, 27320760, 34906519, 22366785, 30385887, 27348543, 32109542, 32227665, 34958143, 36077017, 28857120) -
BS1, BS2, PM3_very_strong, PS3, PS4_supporting -
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Global developmental delay;C1850049:Clinodactyly of the 5th finger;C4021085:Abnormal brain morphology Pathogenic:1
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RBM8A-related disorder Pathogenic:1
The RBM8A c.67+32G>C variant is predicted to interfere with splicing. The c.67+32G>C substitution is found in apparently unaffected individuals at frequencies over 0.5%. However, significant evidence suggests the c.67+32G>C substitution is a “functional polymorphism” and is likely a cause of disease only when paired with a null RBM8A allele, such as a large 1q21.1 deletion that encompasses the RBM8A gene. Large RBM8A deletions found in trans with a functional polymorphism such as c.67+32G>C have been identified in many patients with autosomal recessive thrombocytopenia with absent radius (TAR) (Albers et al. 2012. PubMed ID: 22366785; Boussion et al. 2020. PubMed ID: 32227665). Therefore, we consider this variant to be likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at