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

Genomes: 𝑓 0.0049 ( 5 hom., cov: 31)
Exomes 𝑓: 0.0048 ( 47 hom. )

Consequence

RBM8A
NM_005105.5 intron

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 0.828
Variant links:
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]
LIX1L-AS1 (HGNC:41210): (LIX1L antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP5
Variant 1-145927328-C-G is Pathogenic according to our data. Variant chr1-145927328-C-G is described in ClinVar as [Pathogenic_low_penetrance]. 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, Pathogenic=9, Likely_pathogenic=1, not_provided=1}.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00489 (744/152258) while in subpopulation NFE AF= 0.00723 (492/68018). AF 95% confidence interval is 0.00671. There are 5 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBM8ANM_005105.5 linkc.67+32G>C intron_variant Intron 1 of 5 ENST00000583313.7 NP_005096.1 Q9Y5S9-1A0A023T787
LIX1L-AS1NR_147182.1 linkn.381C>G non_coding_transcript_exon_variant Exon 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBM8AENST00000583313.7 linkc.67+32G>C intron_variant Intron 1 of 5 1 NM_005105.5 ENSP00000463058.2 Q9Y5S9-1
ENSG00000280778ENST00000625258.1 linkc.-30+39C>G intron_variant Intron 1 of 3 5 ENSP00000487094.1 A0A0D9SG24

Frequencies

GnomAD3 genomes
AF:
0.00489
AC:
744
AN:
152140
Hom.:
5
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Radial aplasia-thrombocytopenia syndrome Pathogenic:8Other:1
Apr 25, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 13, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 26, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

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. -

Apr 19, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified as hemizygous in trans with a 414kb Deletion causative for the TAR Syndrome._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 -

Aug 14, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 24, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic, low penetrance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 22, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Apr 19, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BS2, PM3_very_strong, PS3, PS4_supporting -

Jan 26, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 24, 2022
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Global developmental delay;C1850049:Clinodactyly of the 5th finger;C4021085:Abnormal brain morphology Pathogenic:1
Feb 22, 2019
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RBM8A-related disorder Pathogenic:1
Aug 20, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201779890; hg19: chr1-145507765; API