21-34792326-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1252A>C (p.Met418Leu) is a missense variant which has a REVEL score < 0.50 (0.219), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). 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: BP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410147646/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 3.72

Publications

3 publications found

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 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
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 0 ACMG points.

PM2

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

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.1252A>C	p.Met418Leu	missense	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1171A>C	p.Met391Leu	missense	Exon 6 of 6	NP_001001890.1	Q01196-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.1252A>C	p.Met418Leu	missense	Exon 9 of 9	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.1252A>C	p.Met418Leu	missense	Exon 8 of 8	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000344691.8	TSL:1	c.1171A>C	p.Met391Leu	missense	Exon 6 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

142164

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000847

AC:

AN:

1181294

Hom.:

Cov.:

AF XY:

0.00000344

AC XY:

AN XY:

581498

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26936

American (AMR)

AF:

0.00

AC:

AN:

30742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19262

East Asian (EAS)

AF:

0.0000504

AC:

AN:

19850

South Asian (SAS)

AF:

0.00

AC:

AN:

77304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4740

European-Non Finnish (NFE)

AF:

0.00000972

AC:

AN:

926164

Other (OTH)

AF:

0.00

AC:

AN:

45810

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

142164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69088

African (AFR)

AF:

0.00

AC:

AN:

39336

American (AMR)

AF:

0.00

AC:

AN:

14500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

3944

South Asian (SAS)

AF:

0.00

AC:

AN:

3854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64800

Other (OTH)

AF:

0.00

AC:

AN:

2010

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.51

Eigen

Benign

0.097

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

PhyloP100

3.7

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.1

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.019

Polyphen

0.032

Vest4

0.34

MutPred

0.66

Gain of glycosylation at S390 (P = 0.0427)

MVP

0.54

MPC

0.57

ClinPred

0.79

GERP RS

3.9

Varity_R

0.59

gMVP

0.57

Mutation Taster

=43/57

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over