rs555366994

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BS3_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014365/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:1

Conservation

PhyloP100: 7.80

Publications

4 publications found

Variant links:

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

RUNX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.737C>T	p.Thr246Met	missense_variant	Exon 7 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.737C>T	p.Thr246Met	missense_variant	Exon 7 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000479

AC:

AN:

250520

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460918

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726578

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.0000895

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111388

Other (OTH)

AF:

0.0000994

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41490

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T246M variant (also known as c.737C>T), located in coding exon 6 of the RUNX1 gene, results from a C to T substitution at nucleotide position 737. The threonine at codon 246 is replaced by methionine, an amino acid with similar properties. In one functional study, this variant was found to have levels of transcriptional activity that were similar to wild-type (Li Y et al. J Clin Invest, 2021 Jun;131:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Jul 19, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest no damaging effect: transcriptional activity similar to wildtype (Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with B-cell or T-cell acute lymphoblastic leukemia (Li et al., 2021); This variant is associated with the following publications: (PMID: 34166225) -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 246 of the RUNX1 protein (p.Thr246Met). This variant is present in population databases (rs555366994, gnomAD 0.01%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 34166225). ClinVar contains an entry for this variant (Variation ID: 239054). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. Experimental studies have shown that this missense change does not substantially affect RUNX1 function (PMID: 34166225). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Jul 11, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;.;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.2

M;.;.;M;.

PhyloP100

7.8

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

D;D;D;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.064

T;T;T;D;D

Sift4G

Benign

0.13

T;T;T;T;.

Polyphen

0.99

D;B;B;D;.

Vest4

0.53

MVP

0.96

MPC

0.68

ClinPred

0.15

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.31

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over