21-34792326-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied). 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616511/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:4

Conservation

PhyloP100: 3.72

Publications

3 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 -5 ACMG points.

BP4

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.1252A>G	p.Met418Val	missense_variant	Exon 9 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.1252A>G	p.Met418Val	missense_variant	Exon 9 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

142168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000690

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

157236

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000102

AC:

AN:

1181478

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

581588

show subpopulations

African (AFR)

AF:

0.000297

AC:

AN:

26946

American (AMR)

AF:

0.0000325

AC:

AN:

30746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19268

East Asian (EAS)

AF:

0.00

AC:

AN:

19860

South Asian (SAS)

AF:

0.00

AC:

AN:

77306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4740

European-Non Finnish (NFE)

AF:

0.00000216

AC:

AN:

926284

Other (OTH)

AF:

0.0000218

AC:

AN:

45830

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

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:

0.0000984

AC:

AN:

142324

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

69230

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

39444

American (AMR)

AF:

0.0000688

AC:

AN:

14530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

3946

South Asian (SAS)

AF:

0.00

AC:

AN:

3872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64804

Other (OTH)

AF:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000568

Hom.:

Bravo

AF:

0.000155

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 22, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the apparent germline of children with T-cell acute lymphoblastic leukemia (PMID: 34166225); This variant is associated with the following publications: (PMID: 34166225) -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 418 of the RUNX1 protein (p.Met418Val). This variant is present in population databases (rs578042376, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409820). 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. 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. -

Inborn genetic diseases

Benign:1

Dec 19, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Mar 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Sep 18, 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.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied). 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, BP4. -

Acute myeloid leukemia

Benign:1

Aug 31, 2022

Baylor Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;.;.;.

Eigen

Benign

-0.037

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.79

T;T;.;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;.;.;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;T

Polyphen

0.0010

B;B;B;.

Vest4

0.35

MutPred

0.69

Gain of sheet (P = 0.0344);.;.;.;

MVP

0.53

MPC

0.63

ClinPred

0.90

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.44

gMVP

0.68

Mutation Taster

=43/57

disease causing

(source)

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