rs762213305

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.1396A>T variant that results in a Met466Leu missense change has an MAF of 0.001761 (0.1%, 23/13058 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort, which is >0.0015 (0.15%) (BA1). This missense variant has a REVEL score <0.15 (0.149) and SSF and MES predict no effect on splicing (BP4). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014176/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 2.86

Publications

7 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: 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: Benign. The variant received -9 ACMG points.

BP4

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

BA1

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.1396A>T	p.Met466Leu	missense	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1315A>T	p.Met439Leu	missense	Exon 6 of 6	NP_001001890.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RUNX1	ENST00000675419.1	MANE Select	c.1396A>T	p.Met466Leu	missense	Exon 9 of 9	ENSP00000501943.1
RUNX1	ENST00000300305.7	TSL:1	c.1396A>T	p.Met466Leu	missense	Exon 8 of 8	ENSP00000300305.3
RUNX1	ENST00000344691.8	TSL:1	c.1315A>T	p.Met439Leu	missense	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

151094

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:

0.000783

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

GnomAD2 exomes

AF:

0.000162

AC:

AN:

135870

AF XY:

0.000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00191

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1379136

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

681080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31312

American (AMR)

AF:

0.00

AC:

AN:

36048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24494

East Asian (EAS)

AF:

0.000723

AC:

AN:

35984

South Asian (SAS)

AF:

0.00

AC:

AN:

78342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077284

Other (OTH)

AF:

0.0000348

AC:

AN:

57410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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

AF:

0.0000265

AC:

AN:

151216

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000786

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67632

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000793

ExAC

AF:

0.0000635

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)

Hereditary cancer-predisposing syndrome (1)

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.30

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.86

PhyloP100

2.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.42

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.70

Vest4

0.19

MutPred

0.62

Loss of catalytic residue at M439 (P = 0.0082)

MVP

0.39

MPC

1.5

ClinPred

0.14

GERP RS

4.7

Varity_R

0.46

gMVP

0.28

Mutation Taster

=68/32

polymorphism

(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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over