chr21-34834566-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg) variant is reported in gnomAD v3.1 at an MAF of 0.0001064 (0.01%, 7/65790 alleles) in the non-Finish European subpopulation, which does not meet the thresholds for BA1 (≥0.0015) or BS1 (0.00015-0.0015). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID:29365323); however, PS4 cannot be applied as 9 alleles overall are noted in gnomAD. This missense variant has a REVEL score of 0.624, which does not meet the threshold for PP3 (>0.75) or BP4 (<0.15). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014385/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 6.18

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.649G>A	p.Gly217Arg	missense_variant	Exon 7 of 9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.649G>A	p.Gly217Arg	missense_variant	Exon 7 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000557

AC:

AN:

143546

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000253

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:

0.000106

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250576

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135470

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000455

AC:

AN:

1229800

Hom.:

Cov.:

AF XY:

0.0000476

AC XY:

AN XY:

609848

show subpopulations

Gnomad4 AFR exome

AF:

0.0000751

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000108

Gnomad4 SAS exome

AF:

0.0000713

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000557

AC:

AN:

143546

Hom.:

Cov.:

AF XY:

0.0000719

AC XY:

AN XY:

69582

show subpopulations

Gnomad4 AFR

AF:

0.0000253

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:

0.000106

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000806

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G217R variant (also known as c.649G>A), located in coding exon 6 of the RUNX1 gene, results from a G to A substitution at nucleotide position 649. The glycine at codon 217 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in an individual with features consistent with RUNX1 familial platelet disorder with associated myeloid malignancies (Drazer MW et al. Blood Adv, 2018 Jan;2:146-150). 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. -

Acute myeloid leukemia;C1832388:Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jan 31, 2024

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 individuals with various hematologic malignancies (PMID: 24098673, 29365323, 33850299); Published functional studies demonstrate association with a cellular growth advantage (PMID: 24098673); This variant is associated with the following publications: (PMID: 20880108, 24098673, 29365323, 33850299, Nitschke2023[article], 28277065) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Jun 22, 2021

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg) variant is reported in gnomAD v3.1 at an MAF of 0.0001064 (0.01%, 7/65790 alleles) in the non-Finish European subpopulation, which does not meet the thresholds for BA1 (≥0.0015) or BS1 (0.00015-0.0015). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID: 29365323); however, PS4 cannot be applied as 9 alleles overall are noted in gnomAD. This missense variant has a REVEL score of 0.624, which does not meet the threshold for PP3 (>0.75) or BP4 (<0.15). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: none. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 436614). This variant is also known as Gly190Arg. This missense change has been observed in individual(s) with familial platelet disorder with B-cell precursor acute lymphoblastic leukemia and/or hereditary hematopoietic malignancies (PMID: 20880108, 29365323). This variant is present in population databases (rs749004431, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the RUNX1 protein (p.Gly217Arg). -

Acute myeloid leukemia

Uncertain:1

Oct 26, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D;.;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

M;.;.;M;.

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.7

D;D;D;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.059

T;D;D;D;D

Sift4G

Benign

0.39

T;T;T;T;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.89

MutPred

0.21

Loss of ubiquitination at K188 (P = 0.0148);.;.;Loss of ubiquitination at K188 (P = 0.0148);.;

MVP

0.95

MPC

1.7

ClinPred

0.46

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.56

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