rs762292084
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1
This summary comes from the ClinGen Evidence Repository: This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID:19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID:30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID:17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014193/MONDO:0011071/008
Frequency
Consequence
NM_001754.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.1190A>G | p.Gln397Arg | missense_variant | 9/9 | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.1190A>G | p.Gln397Arg | missense_variant | 9/9 | NM_001754.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000793 AC: 12AN: 151324Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000268 AC: 46AN: 171874Hom.: 0 AF XY: 0.000207 AC XY: 19AN XY: 91722
GnomAD4 exome AF: 0.0000481 AC: 68AN: 1414298Hom.: 0 Cov.: 35 AF XY: 0.0000429 AC XY: 30AN XY: 699014
GnomAD4 genome ? AF: 0.0000792 AC: 12AN: 151448Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6AN XY: 74042
ClinVar
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the germline of an individual with pediatric ALL (Cecile Liu et al., 2022); This variant is associated with the following publications: (PMID: 24523240, Liu2022, 19808697, Huang_2009_Abstract) - |
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen Myeloid Malignancy Variant Curation Expert Panel | Jul 07, 2022 | This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID: 19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID: 30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID: 17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. - |
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at