NM_001754.5:c.601dupC

Variant names:

• chr21-34859485-C-CG
• rs2146234527
• NM_001754.5:c.601dupC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5_Supporting PVS1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.601dup (p.Arg201ProfsTer12) is a frameshift variant. The transcript product is predicted to undergo NMD (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has been reported in 1 proband with family history meeting RUNX-1 phenotypic criteria (thrombocytopenia) (PMID 26175287) (PS4_supporting). This variant was also reported in Clinvar in 2021 by Invitae but the affected status of the proband is unknown (Variation ID 1073884). There are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) without use of PM5_Supporting (PMID:35764482) (PM5_supporting).In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_supporting, PM2_supporting, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913189266/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: 4.54
• 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 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.601dupC	p.Arg201ProfsTer12	frameshift	Exon 6 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.520dupC	p.Arg174ProfsTer12	frameshift	Exon 3 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.520dupC	p.Arg174ProfsTer12	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.601dupC	p.Arg201ProfsTer12	frameshift	Exon 6 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.601dupC	p.Arg201ProfsTer12	frameshift	Exon 5 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.520dupC	p.Arg174ProfsTer12	frameshift	Exon 3 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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		4.5

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

Other links and lift over

dbSNP: rs2146234527; hg19: chr21-36231782;