Genetic Variant RUNX1:c.59-46762T>C (chr21-34939725-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001754.5(RUNX1):c.59-46762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 152,116 control chromosomes in the GnomAD database, including 26,634 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.58 ( 26634 hom., cov: 32)

Consequence

RUNX1
NM_001754.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.314

Publications

7 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

RUNX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.59-46762T>C		intron	N/A	NP_001745.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.59-46762T>C	intron	N/A	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.59-46762T>C	intron	N/A	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000416754.1	TSL:1	c.59-46762T>C	intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes

AF:

0.582

AC:

88476

AN:

151998

Hom.:

26589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.741

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.490

Gnomad ASJ

AF:

0.464

Gnomad EAS

AF:

0.707

Gnomad SAS

AF:

0.541

Gnomad FIN

AF:

0.575

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.510

Gnomad OTH

AF:

0.567

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.582

AC:

88576

AN:

152116

Hom.:

26634

Cov.:

AF XY:

0.584

AC XY:

43419

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.741

AC:

30753

AN:

41502

American (AMR)

AF:

0.490

AC:

7495

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

1609

AN:

3468

East Asian (EAS)

AF:

0.708

AC:

3666

AN:

5176

South Asian (SAS)

AF:

0.542

AC:

2613

AN:

4824

European-Finnish (FIN)

AF:

0.575

AC:

6072

AN:

10562

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.510

AC:

34702

AN:

67984

Other (OTH)

AF:

0.565

AC:

1191

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1797

3593

5390

7186

8983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.547

Hom.:

4814

Bravo

AF:

0.582

Asia WGS

AF:

0.579

AC:

2009

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.2

(source)

DANN

Benign

0.61

PhyloP100

-0.31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over