rs771614642

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS3

This summary comes from the ClinGen Evidence Repository: The c.749G>A variant in RUNX1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 250 (p.R250H). A luciferase reporter assaying in U937 cells showed that this variant has normal transcriptional activity, and an EMSA assay using COS7 cells showed that this variant has normal DNA-binding and β-subunit interaction with normal nuclear localization in NIH3T3 cells, indicating that this variant does not impact protein function (PMID:23817177) (BS3). The computational predictor, REVEL, gives a score of 0.488, which is below the threshold of 0.50, evidence that suggests no impact on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS3 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014362/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.749G>A	p.Arg250His	missense_variant	7/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.749G>A	p.Arg250His	missense_variant	7/9		NM_001754.5	ENSP00000501943	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

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:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250026

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000799

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000582

AC:

AN:

1459896

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

725814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000648

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151250

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73814

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 250 of the RUNX1 protein (p.Arg250His). This variant is present in population databases (rs771614642, gnomAD 0.007%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 34166225). ClinVar contains an entry for this variant (Variation ID: 239055). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 12, 2021	- -

Acute myeloid leukemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 17, 2020	This RUNX1 variant (rs771614642) is rare (<0.1%) in a large population dataset (gnomAD: 11/281252 total alleles; 0.004%; no homozygotes) and has not been reported in the literature, to our knowledge. RUNX1 c.749G>A has been reported in ClinVar. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated. Due to insufficient evidence, we consider its clinical significance uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 01, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2019

- -

RUNX1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2023

The RUNX1 c.749G>A variant is predicted to result in the amino acid substitution p.Arg250His. This variant, also described as p.Arg223His (R223H) in an alternative transcript, has been reported as a germline variant in two individuals with pediatric B cell acute lymphoblastic leukemia (B-ALL) and in a 12-year-old patient with thrombocytopenia and myelodysplastic syndrome (MDS) who had refractory cytopenia in childhood (Table 1, Li Y et al 2021. PubMed ID: 34166225; Figure 2, Decker M et al 2022. PubMed ID: 35026845). This variant was also reported as an incidental finding in an individual with Larsen syndrome who did not have thrombocytopenia or abnormal whole blood cell counts (Figure 2, Decker M et al 2022. PubMed ID: 35026845). In vitro functional studies suggest that DNA binding, β-subunit interaction, subcellular localization, and transcriptional activity for this variant are similar to control (Table 1, Koh CP et al 2013. PubMed ID: 23817177; Figure 2, Li Y et al 2021. PubMed ID: 34166225; Figure 1, Decker M et al 2022. PubMed ID: 35026845). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-36206763-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239055/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2023

Published functional studies demonstrate no damaging effect: no significant impact on transactivation activity, DNA binding function, beta-subunit interaction, or subcellular localization (Koh et al., 2013; Li et al., 2021); Identified in the germline of individuals with acute lymphoblastic leukemia (Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R223H; This variant is associated with the following publications: (PMID: 23817177, 34166225) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jun 24, 2024

The c.749G>A variant in RUNX1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 250 (p.R250H). A luciferase reporter assaying in U937 cells showed that this variant has normal transcriptional activity, and an EMSA assay using COS7 cells showed that this variant has normal DNA-binding and β-subunit interaction with normal nuclear localization in NIH3T3 cells, indicating that this variant does not impact protein function (PMID: 23817177) (BS3). The computational predictor, REVEL, gives a score of 0.488, which is below the threshold of 0.50, evidence that suggests no impact on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS3 and BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;.;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.72

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.;.;M;.

MutationTaster

Benign

0.92

D;D;D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Benign

0.11

T;T;T;T;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.58

MVP

0.98

MPC

0.83

ClinPred

0.67

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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