21-34887027-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS3BP2BA1

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID:23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014578/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 32)

Exomes 𝑓: 0.019 ( 357 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:1B:15

Conservation

PhyloP100: 3.34

Publications

48 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: Benign. The variant received -13 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.

BA1

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.167T>C	p.Leu56Ser	missense_variant	Exon 4 of 9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.167T>C	p.Leu56Ser	missense_variant	Exon 4 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1926

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0302

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0176

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0152

AC:

3522

AN:

231814

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00264

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.00175

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.0172

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0188

AC:

27188

AN:

1449220

Hom.:

357

Cov.:

AF XY:

0.0191

AC XY:

13804

AN XY:

721180

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33402

American (AMR)

AF:

0.0113

AC:

505

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26054

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39610

South Asian (SAS)

AF:

0.0308

AC:

2650

AN:

86120

European-Finnish (FIN)

AF:

0.0167

AC:

716

AN:

42812

Middle Eastern (MID)

AF:

0.0215

AC:

124

AN:

5762

European-Non Finnish (NFE)

AF:

0.0197

AC:

21897

AN:

1110748

Other (OTH)

AF:

0.0193

AC:

1158

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1835

3670

5506

7341

9176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.0126

AC:

1925

AN:

152314

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

933

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00385

AC:

160

AN:

41572

American (AMR)

AF:

0.0168

AC:

257

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0302

AC:

146

AN:

4828

European-Finnish (FIN)

AF:

0.0112

AC:

119

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0176

AC:

1198

AN:

68014

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0162

Hom.:

Bravo

AF:

0.0122

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00275

AC:

ESP6500EA

AF:

0.0146

AC:

124

ExAC

AF:

0.0148

AC:

1760

Asia WGS

AF:

0.0120

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1Benign:6

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2019

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is >/= 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBF-beta binding and sub-cellular localization (BS3; PMID: 23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP2. -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RUNX1: PP3, BS1, BS2 -

Jul 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31385734, 31289210, 11921279, 21343560, 27106701, 22753902, 28386644) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Acute myeloid leukemia

Pathogenic:1Benign:1

Nadeem Sheikh Lab, University of the Punjab

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 22, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RUNX1-related disorder

Benign:1

Oct 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Oct 21, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.41

T;.;.;.;.;.;T

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T;.;T;T;T;T

MetaRNN

Benign

0.0049

T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

0.93

L;.;.;.;L;.;.

PhyloP100

3.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.54

N;N;N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.51

T;T;T;T;T;T;T

Sift4G

Benign

0.44

T;T;T;T;T;.;T

Polyphen

1.0

D;P;P;.;B;.;.

Vest4

0.088

MPC

1.7

ClinPred

0.068

GERP RS

5.0

PromoterAI

0.021

Neutral

(source)

Varity_R

0.17

gMVP

0.66

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