rs111527738

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP2BA1BS3

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:11

Conservation

PhyloP100: 3.34

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP2

BS3

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.167T>C	p.Leu56Ser	missense_variant	4/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.167T>C	p.Leu56Ser	missense_variant	4/9		NM_001754.5	A1	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

GnomAD3 exomes

AF:

0.0152

AC:

3522

AN:

231814

Hom.:

AF XY:

0.0169

AC XY:

2168

AN XY:

128042

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 SAS exome

AF:

0.0314

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

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0308

Gnomad4 FIN exome

AF:

0.0167

Gnomad4 NFE exome

AF:

0.0197

Gnomad4 OTH exome

AF:

0.0193

GnomAD4 genome

AF:

0.0126

AC:

1925

AN:

152314

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

933

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00385

Gnomad4 AMR

AF:

0.0168

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0302

Gnomad4 FIN

AF:

0.0112

Gnomad4 NFE

AF:

0.0176

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0165

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:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1Benign:5

Benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Jul 26, 2019	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. -
Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 08, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2019	This variant is associated with the following publications: (PMID: 31385734, 31289210, 11921279, 21343560, 27106701, 22753902, 28386644) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RUNX1: PP3, BS1, BS2 -

Acute myeloid leukemia

Pathogenic:1Benign:1

Likely pathogenic, no assertion criteria provided	clinical testing	Nadeem Sheikh Lab, University of the Punjab	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

RUNX1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2019

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

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 21, 2020

- -

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

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;.;.

MutationTaster

Benign

0.90

D;D;N;N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over