chr21-34834585-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.630A>G (p.Leu210=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014389/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 synonymous

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1B:2

Conservation

PhyloP100: 2.62

Publications

1 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: Uncertain_significance. The variant received -1 ACMG points.

BP4

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.630A>G	p.Leu210Leu	synonymous_variant	Exon 7 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.630A>G	p.Leu210Leu	synonymous_variant	Exon 7 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151144

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250146

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1459988

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.0000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4660

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000198

AC:

AN:

151144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40980

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67926

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000306

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Mar 26, 2025

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.5(RUNX1):c.630A>G (p.Leu210=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. -

Inborn genetic diseases

Benign:1

Nov 26, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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 hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.55

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over