Genetic Variant NM_001754.5:c.58+39324G>A (chr21-35009518-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+39324G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,178 control chromosomes in the GnomAD database, including 1,162 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 0.12 ( 1162 hom., cov: 32)

Consequence

RUNX1
NM_001754.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0470

Publications

3 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.58+39324G>A		intron	N/A	NP_001745.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RUNX1	ENST00000675419.1	MANE Select	c.58+39324G>A	intron	N/A	ENSP00000501943.1
RUNX1	ENST00000300305.7	TSL:1	c.58+39324G>A	intron	N/A	ENSP00000300305.3
RUNX1	ENST00000416754.1	TSL:1	c.58+39324G>A	intron	N/A	ENSP00000405158.1

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17839

AN:

152060

Hom.:

1161

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.0637

Gnomad AMR

AF:

0.0756

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.00673

Gnomad SAS

AF:

0.0637

Gnomad FIN

AF:

0.0815

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.117

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

GnomAD4 genome

AF:

0.117

AC:

17856

AN:

152178

Hom.:

1162

Cov.:

AF XY:

0.113

AC XY:

8407

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.159

AC:

6580

AN:

41500

American (AMR)

AF:

0.0755

AC:

1155

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

474

AN:

3472

East Asian (EAS)

AF:

0.00674

AC:

AN:

5192

South Asian (SAS)

AF:

0.0638

AC:

308

AN:

4828

European-Finnish (FIN)

AF:

0.0815

AC:

862

AN:

10580

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8103

AN:

67992

Other (OTH)

AF:

0.116

AC:

244

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

809

1617

2426

3234

4043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.115

Hom.:

595

Bravo

AF:

0.118

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.5

(source)

DANN

Benign

0.78

PhyloP100

0.047

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over