rs1555884845
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5_SupportingPS4_SupportingPVS1_Strong
This summary comes from the ClinGen Evidence Repository: NM_001754.5:c.1283dup (p.Leu429fs) is a frameshift variant which is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region is critical to protein function (PVS1_strong). This variant is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; SCV000550167.3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM5_supporting, PM2_supporting, PVS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616491/MONDO:0011071/008
Frequency
Consequence
NM_001754.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.1283_1284insT | p.Leu429ProfsTer171 | frameshift_variant | 9/9 | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.1283_1284insT | p.Leu429ProfsTer171 | frameshift_variant | 9/9 | NM_001754.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 15, 2020 | In summary, this variant is a novel last exon frameshift with an uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant disrupts the VWRPY motif (AAs 476-480) of the RUNX1 protein, which is required for binding to the transcriptional co-repressor Transducin-like enhancer of split (PMID: 9837750, 15749889). Although this motif is required for proper regulation of some RUNX1 target genes (PMID: 15749889, 14504086), deletion of this sequence does not significantly impact hematopoietic development or viability in mice (PMID: 14504086, 10594034). Therefore, the clinical significance of disrupting this domain is uncertain. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RUNX1-related disease. This sequence change inserts 1 nucleotide in exon 9 of the RUNX1 mRNA (c.1283dupT), causing a frameshift at codon 429. This change is expected to alter the last 52 amino acids and to extend the RUNX1 protein beyond the natural translational stop signal by 119 amino acids (p.Leu429Profs*171). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at