Genetic Variant RUNX1:c.58+32852G>A (chr21-35015990-C-T) – 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.58+32852G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,044 control chromosomes in the GnomAD database, including 9,964 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 0.35 ( 9964 hom., cov: 32)

Consequence

RUNX1
NM_001754.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.432

Publications

5 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=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.426 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.58+32852G>A		intron	N/A	NP_001745.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.58+32852G>A	intron	N/A	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.58+32852G>A	intron	N/A	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000416754.1	TSL:1	c.58+32852G>A	intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52730

AN:

151926

Hom.:

9963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.277

Gnomad EAS

AF:

0.205

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.477

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.430

Gnomad OTH

AF:

0.326

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

GnomAD4 genome

AF:

0.347

AC:

52762

AN:

152044

Hom.:

9964

Cov.:

AF XY:

0.346

AC XY:

25722

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.239

AC:

9910

AN:

41484

American (AMR)

AF:

0.294

AC:

4497

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.277

AC:

962

AN:

3470

East Asian (EAS)

AF:

0.205

AC:

1060

AN:

5170

South Asian (SAS)

AF:

0.205

AC:

989

AN:

4834

European-Finnish (FIN)

AF:

0.477

AC:

5031

AN:

10548

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.430

AC:

29205

AN:

67940

Other (OTH)

AF:

0.324

AC:

684

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1761

3522

5282

7043

8804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.364

Hom.:

1787

Bravo

AF:

0.332

Asia WGS

AF:

0.195

AC:

681

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.43

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