rs1555899813
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001754.5(RUNX1):c.216_217insGG(p.Ser73GlyfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R72R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
RUNX1
NM_001754.5 frameshift
NM_001754.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.51
Genes affected
RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 21-34886977-T-TCC is Pathogenic according to our data. Variant chr21-34886977-T-TCC is described in ClinVar as [Pathogenic]. Clinvar id is 463988.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.216_217insGG | p.Ser73GlyfsTer50 | frameshift_variant | 4/9 | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.216_217insGG | p.Ser73GlyfsTer50 | frameshift_variant | 4/9 | NM_001754.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen Myeloid Malignancy Variant Curation Expert Panel | Aug 01, 2019 | The NM_001754.4:c.215_216dup (p.Ser73Glyfs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000638134.1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2, PS4_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 09, 2019 | This sequence change creates a premature translational stop signal (p.Ser73Glyfs*50) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant has not been reported in the literature in individuals with RUNX1-related disease. ClinVar contains an entry for this variant (Variation ID: 463988). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at