ClinVar Genomic variation as it relates to human health
NM_005105.5(RBM8A):c.67+32G>C
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005105.5(RBM8A):c.67+32G>C
Variation ID: 30465 Accession: VCV000030465.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.1 1: 145927328 (GRCh38) [ NCBI UCSC ] 1: 145507765 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 23, 2014 Mar 16, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005105.5:c.67+32G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NR_147182.1:n.381C>G non-coding transcript variant NC_000001.11:g.145927328C>G NC_000001.10:g.145507765G>C NG_032654.2:g.5209G>C LRG_574:g.5209G>C LRG_574t1:c.67+32G>C - Protein change
- Other names
- rs201779890
- IVS1, G-C
- Canonical SPDI
- NC_000001.11:145927327:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00080 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00317
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00492
The Genome Aggregation Database (gnomAD) 0.00518
The Genome Aggregation Database (gnomAD), exomes 0.00547
Exome Aggregation Consortium (ExAC) 0.00638
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LIX1L-AS1 | - | - | - | GRCh38 | - | 109 |
LOC126805851 | - | - | - | GRCh38 | - | 121 |
RBM8A | - | - |
GRCh38 GRCh37 |
21 | 269 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Pathogenic, low penetrance (9) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000023419.27 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 30, 2023 | RCV000172898.19 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2019 | RCV001270062.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2023 | RCV003415732.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Radial aplasia-thrombocytopenia syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711732.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 4
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Likely pathogenic
(Feb 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Clinodactyly of the 5th finger
Global developmental delay Abnormal brain morphology
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448815.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
Clinical Features:
Tall stature (present) , Childhood-onset truncal obesity (present) , Global developmental delay (present) , Macrocephalus (present) , Nystagmus (present) , Severe Myopia (present) , High, … (more)
Tall stature (present) , Childhood-onset truncal obesity (present) , Global developmental delay (present) , Macrocephalus (present) , Nystagmus (present) , Severe Myopia (present) , High, narrow palate (present) , Clinodactyly of the 5th finger (present) , Abnormality of brain morphology (present) , Cerebral venous angioma (present) , Clonus (present) , Intellectual disability, moderate (present) (less)
Sex: female
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Radial aplasia-thrombocytopenia syndrome
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518967.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Apr 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Radial aplasia-thrombocytopenia syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893204.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Radial aplasia-thrombocytopenia syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003925661.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
This variant was identified as hemizygous in trans with a 414kb Deletion causative for the TAR Syndrome._x000D_ Criteria applied: PM3_VSTR, PS3, PP4
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Pathogenic
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001825305.4
First in ClinVar: Sep 08, 2021 Last updated: Sep 07, 2023 |
Comment:
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 … (more)
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 (Albers et al., 2012); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30609409, 27320760, 28857120, 34906519, 22366785, 30385887, 27348543, 32109542, 32227665, 34958143, 36077017) (less)
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Pathogenic, low penetrance
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Radial aplasia-thrombocytopenia syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000833764.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
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. … (more)
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). (less)
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Likely pathogenic
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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RBM8A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115311.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331467.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 31, 2019 |
Sex: mixed
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447335.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Sex: female
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Pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Radial aplasia-thrombocytopenia syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929389.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
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. … (more)
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. (less)
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Pathogenic
(Feb 26, 2012)
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no assertion criteria provided
Method: literature only
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THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044710.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 06, 2016 |
Comment on evidence:
In 12 of 55 patients with thrombocytopenia-absent radius syndrome (TAR; 274000), Albers et al. (2012) identified the presence of the minor allele (C) of a … (more)
In 12 of 55 patients with thrombocytopenia-absent radius syndrome (TAR; 274000), Albers et al. (2012) identified the presence of the minor allele (C) of a SNP in the first intron of the RBM8A gene (chr1:145,507,765, GRCh37). The SNP occurred in compound heterozygosity with a 200-kb deletion including the RBM8A gene and 10 other genes. The minor allele frequency of this intronic SNP was 0.42% in 7,504 healthy individuals of the Cambridge BioResource. This SNP resulted in diminished RBM8A transcription in vitro. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Radial aplasia-thrombocytopenia syndrome
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142304.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
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 … (more)
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. (less)
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probable-pathogenic
(Dec 24, 2022)
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no assertion criteria provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000148357.2
First in ClinVar: Apr 19, 2014 Last updated: Apr 23, 2023 |
Comment:
Converted during submission to Likely pathogenic.
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740449.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953496.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Radial aplasia-thrombocytopenia syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000086919.3
First in ClinVar: Oct 02, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Thrombocytopenia Absent Radius Syndrome. | Adam MP | - | 2023 | PMID: 20301781 |
Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome. | Manukjan G | British journal of haematology | 2017 | PMID: 28857120 |
Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. | Albers CA | Nature genetics | 2012 | PMID: 22366785 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RBM8A | - | - | - | - |
Text-mined citations for rs201779890 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.