NM_001754.5:c.590_597delTGGATGGG

Variant names:

• chr21-34859489-GCCCATCCA-G
• NM_001754.5:c.590_597delTGGATGGG

Variant summary

Our verdict is Pathogenic. The variant received 2 ACMG points: 2P and 0B. PM5_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001754.5(RUNX1):c.590_597del change is a frameshift variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay. This variant is predicted to affect all the biologically relevant transcripts (PVS1). In addition, this is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and it affects AA downstream of c.98 (in transcript NM_001754.4) (PM5_supporting). Although, this has been found in a single patient in a large cohort of AML cases (PMID:27137476), its allele frequency and/or germinal origin is unknown. Therefore, we cannot assess case-study/segregation criteria. In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, and PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2580098634/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

RUNX1-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.590_597delTGGATGGG	p.Val197AlafsTer13	frameshift	Exon 6 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.509_516delTGGATGGG	p.Val170AlafsTer13	frameshift	Exon 3 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.509_516delTGGATGGG	p.Val170AlafsTer13	frameshift	Exon 3 of 5	NP_001116079.1	Q01196-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.590_597delTGGATGGG	p.Val197AlafsTer13	frameshift	Exon 6 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.590_597delTGGATGGG	p.Val197AlafsTer13	frameshift	Exon 5 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.509_516delTGGATGGG	p.Val170AlafsTer13	frameshift	Exon 3 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
1	-	-	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

Other links and lift over

hg19: chr21-36231786;