1-145925876-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 B:1
• 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]

ACMG classification

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: 6350 AN: 152120 Hom.: 457 Cov.: 31

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00730

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0143 AC: 3583 AN: 249874 Hom.: 211 AF XY: 0.0127 AC XY: 1720 AN XY: 135358

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00686

Gnomad SAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000781

Gnomad OTH exome AF: 0.00689

GnomAD4 exome AF: 0.00599 AC: 8751 AN: 1460434 Hom.: 393 Cov.: 31 AF XY: 0.00600 AC XY: 4356 AN XY: 726566

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.00803

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00680

Gnomad4 SAS exome AF: 0.0222

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000553

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0419 AC: 6382 AN: 152238 Hom.: 463 Cov.: 31 AF XY: 0.0411 AC XY: 3056 AN XY: 74432

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00732

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.00485 Hom.: 9

Bravo AF: 0.0463

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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:1 Uncertain:1 Benign: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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs12079762; hg19: chr1-145509217;