rs756010562

Variant names:

• chr21-34792572-A-T
• rs756010562
• NM_001754.5:c.1006T>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1006T>A (p.Phe336Ile) is a missense variant which does not meet any ACMG/AMP criteria. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014222/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 6.93
• 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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

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

ACMG classification

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.1006T>A	p.Phe336Ile	missense	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.925T>A	p.Phe309Ile	missense	Exon 6 of 6	NP_001001890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.1006T>A	p.Phe336Ile	missense	Exon 9 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.1006T>A	p.Phe336Ile	missense	Exon 8 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.925T>A	p.Phe309Ile	missense	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000449 AC: 1 AN: 222644 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1452934 Hom.: 0 Cov.: 35 AF XY: 0.0000152 AC XY: 11 AN XY: 721926

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 84646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1108066

Other (OTH) AF: 0.00 AC: 0 AN: 59954

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000830 AC: 1

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	-	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.013	D
Sift4G	Benign	0.11	T
Polyphen		0.98	D
Vest4		0.47
MutPred		0.37		Gain of phosphorylation at S314 (P = 0.1971)
MVP		0.97
MPC		1.4
ClinPred		0.89	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.89
Mutation Taster		=60/40	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: rs756010562; hg19: chr21-36164869;