21-34792309-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1BP7BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1269C>T (p.Arg423=) is a synonymous variant which has a MAF of 0.0003400 (0.034%, 23/67652 alleles) in the European non-Finnish subpopulation of the gnomAD v3 cohort, meeting the threshold for BS1. This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.62)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014189/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

RUNX1
NM_001754.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: 0.642

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

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

BP7

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

BS1

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.1269C>T	p.Arg423Arg	synonymous	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1188C>T	p.Arg396Arg	synonymous	Exon 6 of 6	NP_001001890.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RUNX1	ENST00000675419.1	MANE Select	c.1269C>T	p.Arg423Arg	synonymous	Exon 9 of 9	ENSP00000501943.1
RUNX1	ENST00000300305.7	TSL:1	c.1269C>T	p.Arg423Arg	synonymous	Exon 8 of 8	ENSP00000300305.3
RUNX1	ENST00000344691.8	TSL:1	c.1188C>T	p.Arg396Arg	synonymous	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes

AF:

0.000410

AC:

AN:

151100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00896

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000340

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000696

AC:

100

AN:

143620

AF XY:

0.000608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000325

Gnomad ASJ exome

AF:

0.00698

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.000559

AC:

778

AN:

1391264

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

377

AN XY:

687008

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31614

American (AMR)

AF:

0.000281

AC:

AN:

35632

Ashkenazi Jewish (ASJ)

AF:

0.00810

AC:

202

AN:

24926

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000176

AC:

AN:

79364

European-Finnish (FIN)

AF:

0.0000233

AC:

AN:

42916

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.000439

AC:

473

AN:

1077760

Other (OTH)

AF:

0.000884

AC:

AN:

57698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000410

AC:

AN:

151222

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

AN XY:

73906

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41252

American (AMR)

AF:

0.000197

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00896

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.000210

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000340

AC:

AN:

67644

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

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:

0.000964

Hom.:

Bravo

AF:

0.000419

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (3)

Acute myeloid leukemia (2)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.1

(source)

DANN

Benign

0.73

PhyloP100

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

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