21-34792189-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP7BP4BP2BA1

This summary comes from the ClinGen Evidence Repository: NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) is a synonymous variant which has a minor allele frequency of 0.1206 (1976/16382 alleles) in the African subpopulation of the gnomAD cohort, meeting the threshold for BA1. It is detected in a homozygous state in 202 individuals in gnomAD (BP2). Splicing predictors SSF and MES indicate no significant impact on the canonical splice site, and no cryptic splice sites are created (BP4). Evolutionary conservation algorithms predict the site as not being conserved (BP7). 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, BP2, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014178/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.045 ( 356 hom., cov: 31)

Exomes 𝑓: 0.016 ( 552 hom. )

Consequence

RUNX1
NM_001754.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -0.485

Publications

6 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 -11 ACMG points.

BP2

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

BP4

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

BP7

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

BA1

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.1389C>G	p.Pro463Pro	synonymous_variant	Exon 9 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.1389C>G	p.Pro463Pro	synonymous_variant	Exon 9 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6873

AN:

151862

Hom.:

349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0457

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.000853

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00925

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0311

AC:

4309

AN:

138592

AF XY:

0.0283

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0552

Gnomad ASJ exome

AF:

0.0616

Gnomad EAS exome

AF:

0.0216

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00925

Gnomad OTH exome

AF:

0.0255

GnomAD4 exome

AF:

0.0157

AC:

21791

AN:

1384492

Hom.:

552

Cov.:

AF XY:

0.0156

AC XY:

10686

AN XY:

683826

show subpopulations

African (AFR)

AF:

0.128

AC:

4048

AN:

31624

American (AMR)

AF:

0.0537

AC:

1962

AN:

36512

Ashkenazi Jewish (ASJ)

AF:

0.0606

AC:

1499

AN:

24740

East Asian (EAS)

AF:

0.0227

AC:

823

AN:

36290

South Asian (SAS)

AF:

0.0292

AC:

2299

AN:

78646

European-Finnish (FIN)

AF:

0.00203

AC:

AN:

33932

Middle Eastern (MID)

AF:

0.0266

AC:

127

AN:

4770

European-Non Finnish (NFE)

AF:

0.00891

AC:

9621

AN:

1080252

Other (OTH)

AF:

0.0233

AC:

1343

AN:

57726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1084

2168

3253

4337

5421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

490

980

1470

1960

2450

<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:

0.0454

AC:

6906

AN:

151978

Hom.:

356

Cov.:

AF XY:

0.0444

AC XY:

3301

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.121

AC:

5024

AN:

41486

American (AMR)

AF:

0.0455

AC:

696

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0616

AC:

214

AN:

3472

East Asian (EAS)

AF:

0.0249

AC:

128

AN:

5144

South Asian (SAS)

AF:

0.0245

AC:

118

AN:

4822

European-Finnish (FIN)

AF:

0.000853

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00925

AC:

628

AN:

67904

Other (OTH)

AF:

0.0374

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

328

657

985

1314

1642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0162

Hom.:

Bravo

AF:

0.0519

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:3

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Nov 22, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

May 02, 2025

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) is a synonymous variant which has a minor allele frequency of 0.1206 (1976/16382 alleles) in the African subpopulation of the gnomAD cohort, meeting the threshold for BA1. It is detected in a homozygous state in 202 individuals in gnomAD (BP2). Splicing predictors SSF and MES indicate no significant impact on the canonical splice site, and no cryptic splice sites are created (BP4). Evolutionary conservation algorithms predict the site as not being conserved (BP7). 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, BP2, BP4, BP7. -

Acute myeloid leukemia

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.2

(source)

DANN

Benign

0.75

PhyloP100

-0.48

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over