chr1-145926179-T-C

Position:

• chr1-145926179-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005105.5(RBM8A):​c.343-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RBM8A NM_005105.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.97

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]

ENSG00000289565 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-145926179-T-C is Pathogenic according to our data. Variant chr1-145926179-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1232306.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM8A	NM_005105.5	c.343-2A>G		splice_acceptor_variant, intron_variant		ENST00000583313.7	NP_005096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM8A	ENST00000583313.7	c.343-2A>G		splice_acceptor_variant, intron_variant		1	NM_005105.5	ENSP00000463058.2
ENSG00000289565	ENST00000632040.1	n.136-2A>G		splice_acceptor_variant, intron_variant		2		ENSP00000488887.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Radial aplasia-thrombocytopenia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto

Sep 08, 2021

In silico analysis of the intronic variant predicted an effect on mRNA processing. According to the ACMG criteria, this variant was classified as pathogenic (PVS1, PM2, PP3). The nucleotide substitution promotes skipping of the entire exon 5, predictably leading to a reading-frame shift and premature termination codon (p.(Gly115Argfs*30)). This variant was found in an dignosed TAR syndrome female patient with a classic disease presentation (hypomegakaryocytic thrombocytopenia and bilateral radial aplasia, in the presence of both thumbs). This novel variant was identified in compound heterozygosity with the already known RBM8A 5'UTR c.-21G>C, implicated in TAR syndrome by Albers et al. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-145508914;