rs1555884845

Positions:

• chr21-34792294-G-GA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5_Supporting PS4_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: NM_001754.5:c.1283dup (p.Leu429fs) is a frameshift variant which is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region is critical to protein function (PVS1_strong). This variant is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; SCV000550167.3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM5_supporting, PM2_supporting, PVS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616491/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.1283_1284insT	p.Leu429ProfsTer171	frameshift_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.1283_1284insT	p.Leu429ProfsTer171	frameshift_variant	9/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 15, 2020

In summary, this variant is a novel last exon frameshift with an uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant disrupts the VWRPY motif (AAs 476-480) of the RUNX1 protein, which is required for binding to the transcriptional co-repressor Transducin-like enhancer of split (PMID: 9837750, 15749889). Although this motif is required for proper regulation of some RUNX1 target genes (PMID: 15749889, 14504086), deletion of this sequence does not significantly impact hematopoietic development or viability in mice (PMID: 14504086, 10594034). Therefore, the clinical significance of disrupting this domain is uncertain. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RUNX1-related disease. This sequence change inserts 1 nucleotide in exon 9 of the RUNX1 mRNA (c.1283dupT), causing a frameshift at codon 429. This change is expected to alter the last 52 amino acids and to extend the RUNX1 protein beyond the natural translational stop signal by 119 amino acids (p.Leu429Profs*171). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555884845; hg19: chr21-36164591;