chr1-145926116-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005105.5(RBM8A):c.404A>G(p.Asn135Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N135H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
RBM8A
NM_005105.5 missense
NM_005105.5 missense
Scores
2
4
Clinical Significance
Conservation
PhyloP100: 4.23
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBM8A | NM_005105.5 | c.404A>G | p.Asn135Ser | missense_variant | 5/6 | ENST00000583313.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBM8A | ENST00000583313.7 | c.404A>G | p.Asn135Ser | missense_variant | 5/6 | 1 | NM_005105.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251468Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727242
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Radial aplasia-thrombocytopenia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 135 of the RBM8A protein (p.Asn135Ser). This variant is present in population databases (rs144062976, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RBM8A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.
MetaRNN
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Vest4
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at