21-34834547-T-C

Variant names:

• chr21-34834547-T-C
• rs780999703
• NM_001754.5:c.668A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS3 BP2

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.668A>G (p.Glu223Gly) is a missense variant predicted to cause the substitution of glutamic acid by glycine at amino acid 223 (p.E223G). The highest population minor allele frequency in gnomAD v2 is 0.0001146 (13/113452 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This variant has also been observed in gnomAD v3/v4 in one homozygous individual of Finnish descent, and there are no known reports of affected patients with homozygous RUNX1 variants, plus RUNX1-null mice do not survive (BP2). The germline variant has been published in 2-3 children with B-ALL (PMID:26580448; PMID:34166225) and in a 22-year-old female with thrombocytopenia (low platelet count) and mild bleeding (menorrhagia), congenital aortic valve abnormality, and periventricular nodular heterotopia of the cerebrum but a negative family history of thrombocytopenia and hematologic malignancy (DOI: 10.1155/2023/4738660). However, the variant's presence in the general population (gnomAD) precludes the application of PS4 at any strength level. The computational predictor REVEL gives a score of 0.799, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. However, in vitro functional data indicate that the mutant protein exhibits normal transcriptional activity in a luciferase reporter assay using U937 cells (~105-115% of WT activity, Fig. 4), normal DNA-binding and β-subunit interaction in an EMSA assay using Cos7 cells (Fig. 2), appropriate nuclear localization in NIH3T3 cells, and normal ubiquitination (Fig. 5) (PMID:23817177) (BS3). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP2 and BS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014381/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.000093 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3
• Conservation: PhyloP100: 6.27
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.668A>G	p.Glu223Gly	missense	Exon 7 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.587A>G	p.Glu196Gly	missense	Exon 4 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.587A>G	p.Glu196Gly	missense	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.668A>G	p.Glu223Gly	missense	Exon 7 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.668A>G	p.Glu223Gly	missense	Exon 6 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.587A>G	p.Glu196Gly	missense	Exon 4 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.0000931 AC: 14 AN: 150354 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250952 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000840

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000719 AC: 105 AN: 1460854 Hom.: 0 Cov.: 32 AF XY: 0.0000757 AC XY: 55 AN XY: 726718

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.000489 AC: 26 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5110

European-Non Finnish (NFE) AF: 0.0000683 AC: 76 AN: 1111982

Other (OTH) AF: 0.0000497 AC: 3 AN: 60330

GnomAD4 genome AF: 0.0000931 AC: 14 AN: 150354 Hom.: 1 Cov.: 31 AF XY: 0.0000957 AC XY: 7 AN XY: 73150

African (AFR) AF: 0.00 AC: 0 AN: 40738

American (AMR) AF: 0.00 AC: 0 AN: 14936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00108 AC: 11 AN: 10202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.29		Loss of solvent accessibility (P = 0.0128)
MVP		0.97
MPC		1.5
ClinPred		0.32	T
GERP RS		3.7
Varity_R		0.40
gMVP		0.43
Mutation Taster		=75/25	polymorphism

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: rs780999703; hg19: chr21-36206844; COSMIC: COSV55894403;