chr21-34859508-G-C

Variant names:

• chr21-34859508-G-C
• rs762702957
• NM_001754.5:c.579C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3 PM2_Supporting PS4_Supporting PM1_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.579C>G (p.Ile193Met) is a missense variant which has a REVEL score ≥ 0.88 (0.88) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID:28927163). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410208005/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 ENST00000675419.1 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 4.66
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675419.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.579C>G	p.Ile193Met	missense	Exon 6 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.498C>G	p.Ile166Met	missense	Exon 3 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.498C>G	p.Ile166Met	missense	Exon 3 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.579C>G	p.Ile193Met	missense	Exon 6 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.579C>G	p.Ile193Met	missense	Exon 5 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.498C>G	p.Ile166Met	missense	Exon 3 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.79		Loss of methylation at K167 (P = 0.053)
MVP		0.96
MPC		1.5
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.86
Mutation Taster		=45/55	disease causing

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: rs762702957; hg19: chr21-36231805; COSMIC: COSV55891564; COSMIC: COSV55891564;