chr21-34887039-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP2

This summary comes from the ClinGen Evidence Repository: NM_001754.4(RUNX1):c.155T>A (p.Met52Lys) is a missense variant which has a MAF of 0.0007121 (0.071%, 840/1,179,678 alleles, including 1 homozygote) in the European (non-Finnish) subpopulation of the gnomAD v4.1.0 cohort, meeting the threshold for BS1 and BP2. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014581/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:7B:2O:1

Conservation

PhyloP100: 6.86

Publications

13 publications found

Variant links:

COSMIC-nc: COSV55868681

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 -5 ACMG points.

BP2

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

BS1

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.155T>A	p.Met52Lys	missense_variant	Exon 4 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.155T>A	p.Met52Lys	missense_variant	Exon 4 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000573

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000258

AC:

AN:

232566

AF XY:

0.000249

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000597

AC:

865

AN:

1449282

Hom.:

Cov.:

AF XY:

0.000560

AC XY:

404

AN XY:

721512

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33464

American (AMR)

AF:

0.0000224

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.0000483

AC:

AN:

41450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000721

AC:

801

AN:

1111670

Other (OTH)

AF:

0.000963

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000270

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000729

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000710

AC:

ExAC

AF:

0.000201

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RUNX1Â¬â€ p.M52K variant was identified in the literature in two individuals with acute myeloid leukemia (Mendler_2013_PMID:23753029; Drazer_2018_PMID:29365323). The variant was identified in dbSNP (ID: rs200431130) and ClinVar (classified as uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel, Invitae, and three other laboratories).Â¬â€ The variant was identified in control databases in 65 of 263936 chromosomes at a frequency of 0.0002463, and was observed at the highest frequency in the European (non-Finnish) population in 61 of 122518 chromosomes (freq: 0.0004979) (Genome Aggregation Database March 6, 2019, v2.1.1).Â¬â€ The p.M52 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity.Â¬â€ The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing.Â¬â€ In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Feb 04, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the germline of individuals with acute myeloid leukemia and acute lymphocytic leukemia in published literature (PMID: 29365323, 28801348, 34166225); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23753029, 29365323, 28801348, 34166225, 37647632) -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1Other:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Likely benign and reported on 06-10-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Uncertain:1

Mar 10, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jul 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M52K variant (also known as c.155T>A), located in coding exon 3 of the RUNX1 gene, results from a T to A substitution at nucleotide position 155. The methionine at codon 52 is replaced by lysine, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with RUNX1 familial platelet disorder with associated myeloid malignancies (Mendler JH et al. Haematologica, 2013 Aug;98:e92-4; Drazer MW et al. Blood Adv, 2018 Jan;2:146-150; Li Y et al. J Clin Invest, 2021 Jun;131:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

RUNX1-related disorder

Uncertain:1

Oct 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RUNX1 c.155T>A variant is predicted to result in the amino acid substitution p.Met52Lys. This variant was reported as a germline variant in individuals with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (Mendler et al. 2013. PubMed ID: 23753029; Drazer et al. 2018. PubMed ID: 29365323; Li et al. 2021. PubMed ID: 34166225). One patient with AML also harbored variants in NPM1 and DNMT3A; therefore, it is unclear whether the RUNX1 variant was the primary cause of disease (Mendler et al. 2013. PubMed ID: 23753029). This variant is reported in 0.050% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-36259336-A-T). It is interpreted as a variant of uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/239044/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Anaplastic ependymoma

Uncertain:1

Aug 29, 2016

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 01, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

May 02, 2025

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.4(RUNX1):c.155T>A (p.Met52Lys) is a missense variant which has a MAF of 0.0007121 (0.071%, 840/1,179,678 alleles, including 1 homozygote) in the European (non-Finnish) subpopulation of the gnomAD v4.1.0 cohort, meeting the threshold for BS1 and BP2. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;.;.;.;.;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;.;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.72

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.;.;.;M;.;.

PhyloP100

6.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;D;D;D;D;D;T

Sift4G

Uncertain

0.0090

D;D;D;T;T;.;D

Polyphen

0.97

D;D;D;.;D;.;.

Vest4

0.70

MVP

0.99

MPC

2.0

ClinPred

0.28

GERP RS

5.0

PromoterAI

0.053

Neutral

(source)

Varity_R

0.88

gMVP

0.87

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

Publications

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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