rs578042376

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616511/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:3

Conservation

PhyloP100: 3.72

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:

RUNX1 (HGNC:):

RUNX1 links:

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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.

BS1

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.1252A>G	p.Met418Val	missense_variant	9/9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.1252A>G	p.Met418Val	missense_variant	9/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

142168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000690

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000102

AC:

AN:

1181478

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

581588

show subpopulations

Gnomad4 AFR exome

AF:

0.000297

Gnomad4 AMR exome

AF:

0.0000325

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000216

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000984

AC:

AN:

142324

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

69230

show subpopulations

Gnomad4 AFR

AF:

0.000330

Gnomad4 AMR

AF:

0.0000688

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000568

Hom.:

Bravo

AF:

0.000155

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2025

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the apparent germline of children with T-cell acute lymphoblastic leukemia (PMID: 34166225); 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

Sep 08, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 418 of the RUNX1 protein (p.Met418Val). This variant is present in population databases (rs578042376, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409820). 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. 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. -

RUNX1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. -

Acute myeloid leukemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;.;.;.

Eigen

Benign

-0.037

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.79

T;T;.;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;T

Polyphen

0.0010

B;B;B;.

Vest4

0.35

MutPred

0.69

Gain of sheet (P = 0.0344);.;.;.;

MVP

0.53

MPC

0.63

ClinPred

0.90

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.44

gMVP

0.68

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