rs1060502579
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2_SupportingPS4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1). This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID:24100448 and 32935436). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). 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, PS4_moderate, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410203333/MONDO:0011071/008
Frequency
Consequence
NM_001754.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.351+1G>T | splice_donor_variant | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.351+1G>T | splice_donor_variant | NM_001754.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Myeloid Malignancy Variant Curation Expert Panel | Dec 09, 2023 | The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1). This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 24100448 and 32935436). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). 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, PS4_moderate, PM2_supporting. - |
Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1
Pathogenic, no assertion criteria provided | research | Birmingham Platelet Group; University of Birmingham | May 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at