21-34834596-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3PS4_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.619C>T (p.Arg207Trp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.8109, PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000436615.1). 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: PS4_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410207207/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:5

Conservation

PhyloP100: 5.87

Publications

0 publications found

Variant links:

COSMIC-nc: COSV55897170

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 Gene-Disease associations (from GenCC):

hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

RUNX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.619C>T	p.Arg207Trp	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.619C>T	p.Arg207Trp	missense_variant	Exon 7 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1288804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

640224

African (AFR)

AF:

0.00

AC:

AN:

28384

American (AMR)

AF:

0.00

AC:

AN:

39752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20114

East Asian (EAS)

AF:

0.00

AC:

AN:

26276

South Asian (SAS)

AF:

0.00

AC:

AN:

84528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1000472

Other (OTH)

AF:

0.00

AC:

AN:

49014

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40978

American (AMR)

AF:

0.00

AC:

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

4938

South Asian (SAS)

AF:

0.00

AC:

AN:

4534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67354

Other (OTH)

AF:

0.00

AC:

AN:

2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:2

Feb 08, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 207 of the RUNX1 protein (p.Arg207Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute myleoid leukemia and thromobocytopenia (PMID: 31309983, 32315381). This variant is also known as c.538C>T (p.Arg180Trp). ClinVar contains an entry for this variant (Variation ID: 436615). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RUNX1 function (PMID: 33692461). 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. -

not specified

Uncertain:1

Jan 13, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Jul 11, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.5(RUNX1):c.619C>T (p.Arg207Trp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.8109, PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000436615.1). 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: PS4_supporting, PM2_supporting, PP3. -

Acute myeloid leukemia

Uncertain:1

Dec 25, 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

0.98

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;.;.;M;.

PhyloP100

5.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.5

D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.72

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.9

Varity_R

0.63

gMVP

0.64

Mutation Taster

=37/63

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over