Genetic Variant RUNX1:c.59-31918A>G (chr21-34924881-T-C) – 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.59-31918A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,088 control chromosomes in the GnomAD database, including 48,511 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 0.78 ( 48511 hom., cov: 31)

Consequence

RUNX1
NM_001754.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.06

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=-0.99).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.905 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.59-31918A>G		intron	N/A	NP_001745.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.59-31918A>G	intron	N/A	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.59-31918A>G	intron	N/A	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000416754.1	TSL:1	c.59-31918A>G	intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes

AF:

0.780

AC:

118559

AN:

151970

Hom.:

48488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.989

Gnomad AMR

AF:

0.827

Gnomad ASJ

AF:

0.886

Gnomad EAS

AF:

0.910

Gnomad SAS

AF:

0.928

Gnomad FIN

AF:

0.874

Gnomad MID

AF:

0.823

Gnomad NFE

AF:

0.895

Gnomad OTH

AF:

0.791

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

GnomAD4 genome

AF:

0.780

AC:

118633

AN:

152088

Hom.:

48511

Cov.:

AF XY:

0.783

AC XY:

58210

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.502

AC:

20788

AN:

41442

American (AMR)

AF:

0.827

AC:

12648

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.886

AC:

3074

AN:

3468

East Asian (EAS)

AF:

0.910

AC:

4703

AN:

5170

South Asian (SAS)

AF:

0.928

AC:

4469

AN:

4816

European-Finnish (FIN)

AF:

0.874

AC:

9253

AN:

10588

Middle Eastern (MID)

AF:

0.827

AC:

243

AN:

294

European-Non Finnish (NFE)

AF:

0.895

AC:

60882

AN:

67996

Other (OTH)

AF:

0.791

AC:

1671

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1074

2147

3221

4294

5368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.854

Hom.:

173582

Bravo

AF:

0.762

Asia WGS

AF:

0.874

AC:

3037

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.21

(source)

DANN

Benign

0.61

PhyloP100

-1.1

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