chr21-34887039-A-T

Position:

chr21-34887039-A-T

Variant summary

Our verdict is Uncertain significance. Variant got -3 ACMG points: 1P and 4B. PP3BS1

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.155T>A (p.Met52Lys) variant has a MAF of 0.00071 (0.071%, 6/8,456 alleles) in the EA Allele subpopulation of the ESP cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.845) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014581/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8B:1O:1

Conservation

PhyloP100: 6.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -3 ACMG points.

PP3

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.155T>A	p.Met52Lys	missense_variant	4/9	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.155T>A	p.Met52Lys	missense_variant	4/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000258

AC:

AN:

232566

Hom.:

AF XY:

0.000249

AC XY:

AN XY:

128548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000597

AC:

865

AN:

1449282

Hom.:

Cov.:

AF XY:

0.000560

AC XY:

404

AN XY:

721512

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000483

Gnomad4 NFE exome

AF:

0.000721

Gnomad4 OTH exome

AF:

0.000963

GnomAD4 genome

AF:

0.000270

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000729

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000710

AC:

ExAC

AF:

0.000201

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Benign:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Jul 26, 2019	The NM_001754.4:c.155T>A (p.Met52Lys) variant has a MAF of 0.00071 (0.071%, 6/8,456 alleles) in the EA Allele subpopulation of the ESP cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.845) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Likely benign and reported on 06-10-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RUNX1Â¬â€ p.M52K variant was identified in the literature in two individuals with acute myeloid leukemia (Mendler_2013_PMID:23753029; Drazer_2018_PMID:29365323). The variant was identified in dbSNP (ID: rs200431130) and ClinVar (classified as uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel, Invitae, and three other laboratories).Â¬â€ The variant was identified in control databases in 65 of 263936 chromosomes at a frequency of 0.0002463, and was observed at the highest frequency in the European (non-Finnish) population in 61 of 122518 chromosomes (freq: 0.0004979) (Genome Aggregation Database March 6, 2019, v2.1.1).Â¬â€ The p.M52 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity.Â¬â€ The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing.Â¬â€ In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2024	Observed in the germline of individuals with acute myeloid leukemia and acute lymphocytic leukemia in published literature (PMID: 29365323, 28801348, 34166225); 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: 23753029, 29365323, 28801348, 34166225) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 10, 2017

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2024

The p.M52K variant (also known as c.155T>A), located in coding exon 3 of the RUNX1 gene, results from a T to A substitution at nucleotide position 155. The methionine at codon 52 is replaced by lysine, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with RUNX1 familial platelet disorder with associated myeloid malignancies (Mendler JH et al. Haematologica, 2013 Aug;98:e92-4; Drazer MW et al. Blood Adv, 2018 Jan;2:146-150; Li Y et al. J Clin Invest, 2021 Jun;131:). This amino acid position is well 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. -

RUNX1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2023

The RUNX1 c.155T>A variant is predicted to result in the amino acid substitution p.Met52Lys. This variant was reported as a germline variant in individuals with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (Mendler et al. 2013. PubMed ID: 23753029; Drazer et al. 2018. PubMed ID: 29365323; Li et al. 2021. PubMed ID: 34166225). One patient with AML also harbored variants in NPM1 and DNMT3A; therefore, it is unclear whether the RUNX1 variant was the primary cause of disease (Mendler et al. 2013. PubMed ID: 23753029). This variant is reported in 0.050% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-36259336-A-T). It is interpreted as a variant of uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/239044/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Anaplastic ependymoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Aug 29, 2016

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;.;.;.;.;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;.;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.72

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.;.;.;M;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;D;D;D;D;D;T

Sift4G

Uncertain

0.0090

D;D;D;T;T;.;D

Polyphen

0.97

D;D;D;.;D;.;.

Vest4

0.70

MVP

0.99

MPC

2.0

ClinPred

0.28

GERP RS

5.0

Varity_R

0.88

gMVP

0.87

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