rs749004431

Positions:

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:6

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.649G>A	p.Gly217Arg	missense_variant	7/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.649G>A	p.Gly217Arg	missense_variant	7/9		NM_001754.5	A1	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:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 16, 2017

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with multiple myeloma, acute myeloid leukemia, and chronic myelogenous leukemia (Yamamoto et al., 2013; Drazer et al., 2018); Published functional studies demonstrate association with a cellular growth advantage (Yamamoto et al., 2013); This variant is associated with the following publications: (PMID: 20880108, 24098673, 28277065, 29365323) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jun 22, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2023

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). 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%). -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2023

- -

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;.

MutationTaster

Benign

0.99

D;D;D;D;D;D

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