rs139428292

Variant names:

• chr1-145927447-C-T
• rs139428292
• NM_005105.5:c.-21G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-145927447-C-T
• chr1-145927447-C-A
• chr1-145927447-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_005105.5(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). ClinVar reports functional evidence for this variant: "SCV000712517: 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)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 31)
  • Exomes 𝑓: 0.026 (583 hom.)
• Consequence: RBM8A NM_005105.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:35 U:1 O:2
• Conservation: PhyloP100: -0.503
• Publications: 40 publications found

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:):

LIX1L-AS1 (HGNC:41210): (LIX1L antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000712517: 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).; SCV000823560: Studies have shown that this variant alters RBM8A gene expression (PMID: 22366785).; SCV001251535: 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).; SCV002495917: literature suggests that this variant affects promoter activity and functions as a hypomorphic allele (Albers 2012 PMID: 22366785).; SCV002572396: variant resulted in decreased promoter activity (Albers_2012).; SCV004232357: 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).; SCV005086694: "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)."; SCV005689250: Functional studies on this variant showed that it reduces gene expression. Electrophoretic mobility shift assays demonstrated altered transcription, luciferase assays confirmed decreased promoter activity in relevant cell lines, while immunoblot analysis revealed reduced Y14 protein levels in TAR syndrome patients (PMID: 22366785).; SCV005876025: One functional study found this variant disrupted transcription factor binding and reduced transcription of RBM8A (Albers 2012). PMID: 22366785; SCV006586117: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 22366785).; SCV001989050: 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); SCV004226716: PS3; SCV004121558: 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. PubMed ID: 22366785; SCV005929730: "In vitro studies have shown that the variant results in decreased RBM8A promoter activity (Albers, 2012)."
• 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 VariationId is 30464.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005105.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM8A	NM_005105.5	MANE Select	c.-21G>A		5_prime_UTR	Exon 1 of 6	NP_005096.1	Q9Y5S9-1
	LIX1L-AS1	NR_147182.1		n.500C>T		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM8A	ENST00000583313.7	TSL:1 MANE Select	c.-21G>A		5_prime_UTR	Exon 1 of 6	ENSP00000463058.2	Q9Y5S9-1
	RBM8A	ENST00000369307.4	TSL:1	c.-21G>A		5_prime_UTR	Exon 1 of 6	ENSP00000358313.3	Q9Y5S9-2
	ENSG00000280778	ENST00000625258.1	TSL:5	c.-30+158C>T		intron	N/A	ENSP00000487094.1	A0A0D9SG24

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

GnomAD2 exomes AF: 0.0181 AC: 4306 AN: 237842 AF XY: 0.0184

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 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

African (AFR) AF: 0.00453 AC: 151 AN: 33358

American (AMR) AF: 0.0126 AC: 544 AN: 43242

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 533 AN: 25888

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39530

South Asian (SAS) AF: 0.00729 AC: 616 AN: 84550

European-Finnish (FIN) AF: 0.0161 AC: 847 AN: 52768

Middle Eastern (MID) AF: 0.0323 AC: 178 AN: 5504

European-Non Finnish (NFE) AF: 0.0302 AC: 33504 AN: 1107788

Other (OTH) AF: 0.0236 AC: 1421 AN: 60092

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

African (AFR) AF: 0.00556 AC: 231 AN: 41534

American (AMR) AF: 0.0148 AC: 226 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4820

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1979 AN: 68018

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0239 Hom.: 16

Bravo AF: 0.0179

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
26	-	-	Radial aplasia-thrombocytopenia syndrome (27)
7	1	-	not provided (9)
1	-	-	Inborn genetic diseases (1)
1	-	-	RBM8A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.2
DANN	Benign	0.89
PhyloP100		-0.50
PromoterAI		-0.0027	Neutral

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

Other links and lift over

dbSNP: rs139428292; hg19: chr1-145507646;