chr21-34834547-T-C

Position:

chr21-34834547-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS3BP2

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.668A>G (p.Glu223Gly) is a missense variant predicted to cause the substitution of glutamic acid by glycine at amino acid 223 (p.E223G). The highest population minor allele frequency in gnomAD v2 is 0.0001146 (13/113452 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This variant has also been observed in gnomAD v3/v4 in one homozygous individual of Finnish descent, and there are no known reports of affected patients with homozygous RUNX1 variants, plus RUNX1-null mice do not survive (BP2). The germline variant has been published in 2-3 children with B-ALL (PMID:26580448; PMID:34166225) and in a 22-year-old female with thrombocytopenia (low platelet count) and mild bleeding (menorrhagia), congenital aortic valve abnormality, and periventricular nodular heterotopia of the cerebrum but a negative family history of thrombocytopenia and hematologic malignancy (DOI: 10.1155/2023/4738660). However, the variant's presence in the general population (gnomAD) precludes the application of PS4 at any strength level. The computational predictor REVEL gives a score of 0.799, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. However, in vitro functional data indicate that the mutant protein exhibits normal transcriptional activity in a luciferase reporter assay using U937 cells (~105-115% of WT activity, Fig. 4), normal DNA-binding and β-subunit interaction in an EMSA assay using Cos7 cells (Fig. 2), appropriate nuclear localization in NIH3T3 cells, and normal ubiquitination (Fig. 5) (PMID:23817177) (BS3). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP2 and BS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014381/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000093 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:3

Conservation

PhyloP100: 6.27

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.

BP2

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 link	c.668A>G	p.Glu223Gly	missense_variant	7/9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.668A>G	p.Glu223Gly	missense_variant	7/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000931

AC:

AN:

150354

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00108

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250952

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135626

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000840

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000719

AC:

105

AN:

1460854

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000489

Gnomad4 NFE exome

AF:

0.0000683

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000931

AC:

AN:

150354

Hom.:

Cov.:

AF XY:

0.0000957

AC XY:

AN XY:

73150

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00108

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	RUNX1: PP3, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2024	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: 26580448, Nitschke2022[poster], Nitschke2023[article], 31289210, 34166225) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2024

The p.E223G variant (also known as c.668A>G), located in coding exon 6 of the RUNX1 gene, results from an A to G substitution at nucleotide position 668. The glutamic acid at codon 223 is replaced by glycine, an amino acid with similar properties. This variant has been reported in several individuals with pediatric acute lymphocytic leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Li Y et al. J Clin Invest, 2021 Jun;131:; Junk SV et al. Haematologica, 2019 Sep;104:e402-e405). This amino acid position is highly 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Sep 24, 2021

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Sep 18, 2024

NM_001754.5(RUNX1):c.668A>G (p.Glu223Gly) is a missense variant predicted to cause the substitution of glutamic acid by glycine at amino acid 223 (p.E223G). The highest population minor allele frequency in gnomAD v2 is 0.0001146 (13/113452 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This variant has also been observed in gnomAD v3/v4 in one homozygous individual of Finnish descent, and there are no known reports of affected patients with homozygous RUNX1 variants, plus RUNX1-null mice do not survive (BP2). The germline variant has been published in 2-3 children with B-ALL (PMID: 26580448; PMID: 34166225) and in a 22-year-old female with thrombocytopenia (low platelet count) and mild bleeding (menorrhagia), congenital aortic valve abnormality, and periventricular nodular heterotopia of the cerebrum but a negative family history of thrombocytopenia and hematologic malignancy (DOI: 10.1155/2023/4738660). However, the variant's presence in the general population (gnomAD) precludes the application of PS4 at any strength level. The computational predictor REVEL gives a score of 0.799, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. However, in vitro functional data indicate that the mutant protein exhibits normal transcriptional activity in a luciferase reporter assay using U937 cells (~105-115% of WT activity, Fig. 4), normal DNA-binding and β-subunit interaction in an EMSA assay using Cos7 cells (Fig. 2), appropriate nuclear localization in NIH3T3 cells, and normal ubiquitination (Fig. 5) (PMID: 23817177) (BS3). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP2 and BS3. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

D;D;.;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;.;.;M;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.1

D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;T;.

Polyphen

1.0

D;P;P;D;.

Vest4

0.68

MutPred

0.29

Loss of solvent accessibility (P = 0.0128);.;.;Loss of solvent accessibility (P = 0.0128);.;

MVP

0.97

MPC

1.5

ClinPred

0.32

GERP RS

3.7

Varity_R

0.40

gMVP

0.43

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