rs199881885

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP7BP2BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.351+15A>G variant has a MAF of 0.00809 (0.809%, 524/64,760 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (8) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.34728 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014545/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 27 hom. )

Consequence

RUNX1
NM_001754.5 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: -1.32

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: 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.351+15A>G		intron_variant	Intron 4 of 8	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.351+15A>G		intron_variant	Intron 4 of 8		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

588

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00578

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00477

AC:

1182

AN:

247738

AF XY:

0.00475

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00569

Gnomad NFE exome

AF:

0.00740

Gnomad OTH exome

AF:

0.00837

GnomAD4 exome

AF:

0.00533

AC:

7777

AN:

1457844

Hom.:

Cov.:

AF XY:

0.00515

AC XY:

3739

AN XY:

725412

show subpopulations

African (AFR)

AF:

0.000781

AC:

AN:

33288

American (AMR)

AF:

0.00363

AC:

162

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00281

AC:

AN:

25980

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39440

South Asian (SAS)

AF:

0.000685

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00580

AC:

308

AN:

53072

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

4978

European-Non Finnish (NFE)

AF:

0.00608

AC:

6755

AN:

1110210

Other (OTH)

AF:

0.00518

AC:

311

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

472

943

1415

1886

2358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<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:

0.00387

AC:

589

AN:

152134

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

276

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41516

American (AMR)

AF:

0.00451

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00578

AC:

393

AN:

67982

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00448

Hom.:

Bravo

AF:

0.00419

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:4

Jul 26, 2019

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_001754.4:c.351+15A>G variant has a MAF of 0.00809 (0.809%, 524/64,760 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is >/= 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (8) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.34728 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. -

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 20, 2017

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acute myeloid leukemia;C1832388:Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Mar 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.66

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

-1.3

PromoterAI

0.012

Neutral

(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

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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