rs1555889947

Variant names:

• chr21-34834471-G-A
• rs1555889947
• NM_001754.5:c.744C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.744C>T (p.Asn248=) is a synonymous variant predicted by SSF and MES to lead to either an increase or a decrease in the canonical splice site score by no more than 10%, with no putative cryptic splice sites created (BP4). However, evolutionary conservation algorithms predict the site as being moderately conserved (PhyloP score: 2.55) and the variant is not the reference nucleotide in one primate and/or three mammal species. This variant is also absent from population databases (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512318594/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 31)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:2
• Conservation: PhyloP100: 3.99
• 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 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.744C>T	p.Asn248Asn	synonymous	Exon 7 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.663C>T	p.Asn221Asn	synonymous	Exon 4 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.663C>T	p.Asn221Asn	synonymous	Exon 4 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.744C>T	p.Asn248Asn	synonymous	Exon 7 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.744C>T	p.Asn248Asn	synonymous	Exon 6 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.663C>T	p.Asn221Asn	synonymous	Exon 4 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)
-	1	-	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1555889947; hg19: chr21-36206768;