chr21-34792163-A-G

Variant names:

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1415T>C (p.Leu472Pro) is a missense variant in the final exon of the protein. MAF of 0.002289 (0.2289%, 23/10046 alleles, gnomad v2.11) in South East Asian population: cohort is ≥ 0.0015 (0.15%) (BA1). The REVEL score= 0.414 (≤0.50) and SpliceAI is ≤0.20 (0.00) (BP4). In summary, this variant meets the 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/CA10014174/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 6.89

Publications

13 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.1415T>C	p.Leu472Pro	missense	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1334T>C	p.Leu445Pro	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.1415T>C	p.Leu472Pro	missense	Exon 9 of 9	ENSP00000501943.1
RUNX1	ENST00000300305.7	TSL:1	c.1415T>C	p.Leu472Pro	missense	Exon 8 of 8	ENSP00000300305.3
RUNX1	ENST00000344691.8	TSL:1	c.1334T>C	p.Leu445Pro	missense	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes

AF:

0.0000792

AC:

AN:

151588

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:

0.00214

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

115798

AF XY:

0.000239

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000187

AC:

255

AN:

1364118

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

119

AN XY:

671970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30330

American (AMR)

AF:

0.00

AC:

AN:

33808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23654

East Asian (EAS)

AF:

0.00692

AC:

245

AN:

35408

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4248

European-Non Finnish (NFE)

AF:

0.00000467

AC:

AN:

1071158

Other (OTH)

AF:

0.0000703

AC:

AN:

56880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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:

0.0000791

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00214

AC:

AN:

5132

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000264

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3474

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 thrombocytopenia and hematologic cancer predisposition syndrome (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

RUNX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.6

PhyloP100

6.9

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.35

MutPred

0.64

Loss of stability (P = 0.0241)

MVP

0.57

MPC

2.0

ClinPred

0.14

GERP RS

4.8

Varity_R

0.87

gMVP

0.65

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

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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

Computational scores

Splicing

Publications

Other links and lift over