rs759078185
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4
This summary comes from the ClinGen Evidence Repository: NM_001754.4(RUNX1):c.56G>A (p.Arg19Lys) is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.R19K); note that this variant is in the 5' UTR, c.-161732G>A, of NM_001001890.3. The variant has been reported in a 69-year-old patient with NPM1-mutated, cytogenetically normal AML at a VAF=53% (PMID:31367767) and in a patient with CMML (PMID:24030381, Supplementary Table 2); however, germline origin is unclear for these cases. The highest population minor allele frequency in gnomAD v2 is 0.006966% (9/129192 alleles) in the non-Finnish European population, and the variant has also been reported in 1/1358 controls from a study evaluating 57 individuals with cutaneous melanoma and 2 other primaries (PMID:29641532, Supplementary Table 3). To our knowledge, functional assays have not been reported for this variant, but the computational predictor REVEL gives a score of 0.456, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy-VCEP: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014724/MONDO:0011071/008
Frequency
Consequence
NM_001754.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.56G>A | p.Arg19Lys | missense_variant, splice_region_variant | 2/9 | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.56G>A | p.Arg19Lys | missense_variant, splice_region_variant | 2/9 | NM_001754.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152148Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251478Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461138Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 726928
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152148Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 28, 2020 | DNA sequence analysis of the RUNX1 gene demonstrated a sequence change, c.56G>A, in exon 2 that results in an amino acid change, p.Arg19Lys. This sequence change does not appear to have been previously described in patients with RUNX1-related disorders and has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs759078185). The p.Arg19Lys change affects a poorly conserved amino acid residue located in a domain of the RUNX1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg19Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg19Lys change remains unknown at this time. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 19 of the RUNX1 protein (p.Arg19Lys). This variant is present in population databases (rs759078185, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409814). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Acute myeloid leukemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at