1-145927447-C-T

Position:

• chr1-145927447-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5 BP4 BS1_Supporting

The ENST00000583313.7(RBM8A):​c.-21G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,604,966 control chromosomes in the GnomAD database, including 616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 31)
  • Exomes 𝑓: 0.026 (583 hom.)
• Consequence: RBM8A ENST00000583313.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:28 U:1 O:2
• Conservation: PhyloP100: -0.503

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 Likely_benign. Variant got -1 ACMG points.

• PP5: Variant 1-145927447-C-T is Pathogenic according to our data. Variant chr1-145927447-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 30464.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic_low_penetrance=1, Pathogenic=16, other=1, Uncertain_significance=1, Likely_pathogenic=3}.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0184 (2808/152246) while in subpopulation NFE AF= 0.0291 (1979/68018). AF 95% confidence interval is 0.028. There are 33 homozygotes in gnomad4. There are 1307 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/exons	MANE	Protein	UniProt
RBM8A	NM_005105.5	c.-21G>A		5_prime_UTR_variant	1/6	ENST00000583313.7	NP_005096.1
LIX1L-AS1	NR_147182.1	n.500C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM8A	ENST00000583313.7	c.-21G>A		5_prime_UTR_variant	1/6	1	NM_005105.5	ENSP00000463058.2
ENSG00000280778	ENST00000625258.1	c.-30+158C>T		intron_variant		5		ENSP00000487094.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2806 AN: 152128 Hom.: 33 Cov.: 31

Gnomad AFR AF: 0.00558

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0181 AC: 4306 AN: 237842 Hom.: 61 AF XY: 0.0184 AC XY: 2361 AN XY: 128260

Gnomad AFR exome AF: 0.00520

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00731

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0260 AC: 37795 AN: 1452720 Hom.: 583 Cov.: 30 AF XY: 0.0257 AC XY: 18547 AN XY: 721608

Gnomad4 AFR exome AF: 0.00453

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0206

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00729

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.0302

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0184 AC: 2808 AN: 152246 Hom.: 33 Cov.: 31 AF XY: 0.0176 AC XY: 1307 AN XY: 74448

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0291

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0217 Hom.: 9

Bravo AF: 0.0179

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:28 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Radial aplasia-thrombocytopenia syndrome Pathogenic:21 Other:1

Pathogenic, no assertion criteria provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 12, 2022	This variant has been reported in the literature in numerous individuals with thrombocytopenia-absent radius (TAR) syndrome, most often as a compound heterozygote in trans with a recurrent 200kb deletion (Selected publications: Albers 2012 PMID: 22366785; Bottillo 2013 PMID: 24053387; Bastida 2018 PMID: 28983057; Boussion 2020 PMID: 32227665) and is present in the GeneReviews entry for this gene (Toriello 2016 PMID: 20301781). Of note, individuals who carry this variant in the homozygous state have typically not been found in association with disease (Toriello 2016 PMID: 20301781). This variant is present in the Genome Aggregation Database (Highest reported MAF: 2.8% [3411/122966], including in 64 total homozygotes (https://gnomad.broadinstitute.org/variant/1-145507646-G-A?dataset=gnomad_r2_1). This variant is also present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID: 30464). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant occurs in the 5' UTR of this gene and does not change the coding sequence; however, literature suggests that this variant affects promoter activity and functions as a hypomorphic allele (Albers 2012 PMID: 22366785). In summary, although this variant occurs at a high minor allele frequency, there is significant evidence suggesting a disease-causing impact of this variant and it is thus classified as pathogenic, but may be best regarded as a a hypomorphic allele. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous c.-21G>A variant in RBM8A was identified by our study in one individual in the compound heterozygous state, with a copy number variant, with Thrombocytopenia Absent Radius syndrome (TAR). This variant has been identified in 1.812% (4778/2263746) of chromosomes, including 63 homozygous individuals, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139428292). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role in the compound heterozygous state. The c.-21G>A variant in RBM8A has been reported in the heterozygous state, with a deletion or frameshift variant, in 39 individuals with TAR (PMID: 22366785). Trio exome analysis in the literature showed this variant to be de novo in at least 8 individuals (PMID: 22366785). The presence of this variant in combination with a reported pathogenic variant and in an individual with TAR increases the likelihood that the c.-21G>A variant is pathogenic in the compound heterozygous state, though not the homozygous state. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 30464). The c.-21G>A variant is pathogenic based off of our findings, multiple de novo reports in the literature, and ClinVar. ACMG/AMP Criteria applied: PM3_Strong, PM6_Strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Thrombocytopaenia-absent radius syndrome (TARS, MIM#605313). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. This variant results in reduced expression of the Y14 protein (PMID: 22366785). (SP) 0253 - This variant is hemizygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 4703 heterozygotes, 64 homozygotes). Individuals homozygous for this variant do not have features of TAR syndrome. (PMID: 20301781). (I) 0311 - An alternative nucleotide change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant commonly reported in trans with a 1q21.1 deletion in patients with TARS (PMID: 22366785, PMID 28857120, PMID 32227665 and ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant results in decreased RBM8A promoter activity and reduced expression of the encoded protein (Y14) in platelets from TARS patients (PMID: 22366785). (SP) 1101 - Very strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2022	Variant summary: RBM8A c.-21G>A is located in the untranslated mRNA region upstream of the initiation codon. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.018 in 237842 control chromosomes in the gnomAD database, including 61 homozygotes. c.-21G>A has been reported in the literature in multiple individuals affected with Radial Aplasia-Thrombocytopenia Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant resulted in decreased promoter activity (Albers_2012). Twelve 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Apr 11, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The RBM8A c.-21G>A (p.?) variant is a pathogenic variant that is located in the 5' noncoding, untranslated region (5' UTR) of the RBM8A gene. This variant is associated with reduced RBM8A gene activity, and is a mild (hypomorphic) variant that is associated with thrombocytopenia absent radius (TAR) syndrome only in the presence of a more severe, loss-of-function RBM8A variant in trans (PMID: 22366785; 24053387). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Apr 05, 2021	The c.-21G>A variant in the RBM8A gene is a reported cause of thrombocytopenia absent radius syndrome (Albers et al., 2012; Boussion et al., 2020). This variant in the homozygous state does not cause thrombocytopenia absent radius syndrome; however, this variant in conjunction with a loss of function variant is a common cause of thrombocytopenia absent radius syndrome. The c.-21G>A variant was determined to be in trans with a pathogenic variant (1q21.1 deletion) consistent with autosomal recessive inheritance (Albers et al., 2012; Boussion et al., 2020). The presence of this variant with an established disease-causing variant on the opposite allele increases suspicion for its pathogenicity. This variant has been identified in 3,411/122,966 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is consistent with a recessive carrier frequency for a mild allele. Well-established in vitro functional studies of the c.-21G>A variant strongly suggest it reduces protein expression that is sufficient to be disease-causing (Albers et al., 2012; Boussion et al., 2020). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.-21G>A variant as pathogenic for autosomal recessive thrombocytopenia absent radius (TAR) syndrome based on the information above. [ACMG evidence codes used: PS3; PM3_verystrong] -
Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 15, 2023	The c.-21G>A variant in RBM8A has been reported in the compound heterozygous state in numerous individuals with thrombocytopenia with absent radius (TAR) syndrome. The majority of these individuals had a submicroscopic deletion encompassing the RBM8A gene on the other allele, while the remaining cases had different truncating variants on the opposite allele (Albers 2012 PMID: 22366785, Bottillo 2013 PMID: 24053387, Manukjan 2017 PMID: 28857120). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID #30464) and has been identified in 2.9% (1979/68026) of European chromosomes, including 27 homozygotes in gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role in the compound heterozygous state. This variant is located in the 5'UTR of the RBM8A gene and does not affect the coding sequence. In vitro studies suggest that it affects promoter activity and may lead to reduced gene expression, functioning as a hypomorphic allele (Albers 2012 PMID: 22366785). Compound heterozygosity for a hypomorph (this variant) and a loss of function variant in RBM8A is strongly associated with TAR syndrome; however, individuals that are homozygous for the c.-21G>A variant are not expected to have features of TAR syndrome. In summary, despite its frequency in the general population, this variant meets criteria to be pathogenic for autosomal recessive TAR syndrome when in compound heterozygosity with another more severe loss of function RBM8A variant. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate. -
Pathogenic, low penetrance, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This variant occurs in a non-coding region of the RBM8A gene. It does not change the encoded amino acid sequence of the RBM8A protein. This variant is present in population databases (rs139428292, gnomAD 2.8%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with TAR Syndrome (PMID: 22366785, 24220582, 27320760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30464). Studies have shown that this variant alters RBM8A gene expression (PMID: 22366785). 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, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jun 17, 2024	PS3, PS4_MOD - It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 30464). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 09, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not provided Pathogenic:6 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2024	Published functional studies suggest a damaging effect due to disruption of transcription factor binding and reduced transcription of RBM8A, indicating that this is a hypomorphic allele (PMID: 22366785); Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; This variant is associated with the following publications: (PMID: 25813282, 24053387, 28556904, 22366785, 32981126, 27320760, 24220582, 30385887, 30609409, 29595812, 20301781, 32227665, 28983057, 32333414, 28857120, 36939041, 34323054, 36077017) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 19, 2024	BS1, BS2, PP5, PM3_strong, PS3, PS4_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RBM8A: PS4:Moderate, PS3:Supporting -
other, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 22, 2020	- Reduced function allele

RBM8A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The RBM8A c.-21G>A variant is located in the 5' untranslated region. The c.-21G>A substitution is found in apparently unaffected individuals at frequencies over 2.7% (Albers et al. 2012. PubMed ID: 22366785; see also gnomAD database). However, significant evidence suggests the c.-21G>A substitution is a “functional polymorphism” and that when paired with a null RBM8A allele, such as a large 1q21.1 deletion identified in most TAR patients, is likely a cause of thrombocytopenia with absent radius (TAR) (Albers et al. 2012. PubMed ID: 22366785; Bottillo et al. 2013. PubMed ID: 24053387). Using a cell-based, biochemical assay, studies from Albers et al. 2012 show that the c.-21G>A substitution may decrease transcription of a reporter gene and therefore, when found in patients also harboring a null RBM8A allele, may result in reduction of RBM8A protein to levels below a critical threshold required by some cell types. In summary, the c.-21G>A variant has been found in a high proportion of patients with TAR who also have a large deletion on the opposite allele that includes the RBM8A gene. However, individuals that are homozygous for the c.-21 G>A variant are not expected to have features of TAR syndrome (Bottillo et al. 2013. PubMed ID: 24053387; see also gnomAD database). Based on the collective evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.2
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139428292; hg19: chr1-145507646;