rs201779890

Positions:

• chr1-145927328-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP5_Strong BP4

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 other (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (47 hom.)
• Consequence: RBM8A NM_005105.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 0.828

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]

ENSG00000280778 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP5: Variant 1-145927328-C-G is Pathogenic according to our data. Variant chr1-145927328-C-G is described in ClinVar as [other]. Clinvar id is 30465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic_low_penetrance=1, not_provided=1, Pathogenic=9, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM8A	NM_005105.5	c.67+32G>C		intron_variant		ENST00000583313.7	NP_005096.1
LIX1L-AS1	NR_147182.1	n.381C>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM8A	ENST00000583313.7	c.67+32G>C		intron_variant		1	NM_005105.5	ENSP00000463058.2
ENSG00000280778	ENST00000625258.1	c.-30+39C>G		intron_variant		5		ENSP00000487094.1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 744 AN: 152140 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00547 AC: 1281 AN: 234162 Hom.: 8 AF XY: 0.00545 AC XY: 688 AN XY: 126236

Gnomad AFR exome AF: 0.000480

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000829

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000380

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.00671

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00482 AC: 6994 AN: 1451544 Hom.: 47 Cov.: 31 AF XY: 0.00475 AC XY: 3422 AN XY: 720966

Gnomad4 AFR exome AF: 0.000600

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000495

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00430

GnomAD4 genome AF: 0.00489 AC: 744 AN: 152258 Hom.: 5 Cov.: 31 AF XY: 0.00533 AC XY: 397 AN XY: 74438

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.00723

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00639 Hom.: 2

Bravo AF: 0.00317

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Radial aplasia-thrombocytopenia syndrome Pathogenic:8 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 19, 2023	This variant was identified as hemizygous in trans with a 414kb Deletion causative for the TAR Syndrome._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2024	BS1, BS2, PM3_very_strong, PS3, PS4_supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2016	- -
Likely pathogenic, no assertion criteria provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 24, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Global developmental delay;C1850049:Clinodactyly of the 5th finger;C4021085:Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Feb 22, 2019

- -

RBM8A-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2024

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.72

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201779890; hg19: chr1-145507765;