21-34834478-G-A

Position:

chr21-34834478-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS3_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014365/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:1

Conservation

PhyloP100: 7.80

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 Likely_benign. Variant got -2 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.737C>T	p.Thr246Met	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.737C>T	p.Thr246Met	missense_variant	7/9		NM_001754.5	ENSP00000501943	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250520

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460918

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726578

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2023

Published functional studies suggest no damaging effect: transcriptional activity similar to wildtype (Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with B-cell or T-cell acute lymphoblastic leukemia (Li et al., 2021); This variant is associated with the following publications: (PMID: 34166225) -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 246 of the RUNX1 protein (p.Thr246Met). This variant is present in population databases (rs555366994, gnomAD 0.01%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 34166225). ClinVar contains an entry for this variant (Variation ID: 239054). 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. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jul 11, 2024

NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;.;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.2

M;.;.;M;.

MutationTaster

Benign

0.95

D;D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

D;D;D;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.064

T;T;T;D;D

Sift4G

Benign

0.13

T;T;T;T;.

Polyphen

0.99

D;B;B;D;.

Vest4

0.53

MVP

0.96

MPC

0.68

ClinPred

0.15

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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