rs555366994
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS3_SupportingBP4
This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014365/MONDO:0011071/008
Frequency
Consequence
NM_001754.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151946Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250520Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135398
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1460918Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 726578
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The p.T246M variant (also known as c.737C>T), located in coding exon 6 of the RUNX1 gene, results from a C to T substitution at nucleotide position 737. The threonine at codon 246 is replaced by methionine, an amino acid with similar properties. In one functional study, this variant was found to have levels of transcriptional activity that were similar to wild-type (Li Y et al. J Clin Invest, 2021 Jun;131:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
not provided Uncertain:1
Published functional studies suggest no damaging effect: transcriptional activity similar to wildtype (Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with B-cell or T-cell acute lymphoblastic leukemia (Li et al., 2021); This variant is associated with the following publications: (PMID: 34166225) -
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 246 of the RUNX1 protein (p.Thr246Met). This variant is present in population databases (rs555366994, gnomAD 0.01%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 34166225). ClinVar contains an entry for this variant (Variation ID: 239054). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. Experimental studies have shown that this missense change does not substantially affect RUNX1 function (PMID: 34166225). 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. -
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1
NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at