1-145926041-C-T

Variant names:

• chr1-145926041-C-T
• NM_005105.5:c.479G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005105.5(RBM8A):​c.479G>A​(p.Arg160Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RBM8A NM_005105.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM8A	NM_005105.5	c.479G>A	p.Arg160Lys	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000583313.7	NP_005096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM8A	ENST00000583313.7	c.479G>A	p.Arg160Lys	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_005105.5	ENSP00000463058.2
ENSG00000289565	ENST00000632040.1	n.272G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	2		ENSP00000488887.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Radial aplasia-thrombocytopenia syndrome Uncertain:1

Dec 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with clinical features of thrombocytopenia-absent radius syndrome (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine with lysine at codon 160 of the RBM8A protein (p.Arg160Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.083	T;T;.
LIST_S2	Benign	0.82	.;T;T
MetaRNN	Benign	0.31	T;T;T
PROVEAN	Benign	-1.1	.;.;N
Sift	Benign	0.20	.;.;T
Sift4G	Benign	0.14	T;T;T
Vest4		0.32
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: -2

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: chr1-145509052;