rs2243988

Variant names:

• chr21-34830143-T-C
• rs2243988
• NM_001754.5:c.805+4267A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001754.5(RUNX1):​c.805+4267A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 152,078 control chromosomes in the GnomAD database, including 18,629 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 0.45 (18629 hom., cov: 31)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78
• Publications: 7 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 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.805+4267A>G		intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.724+4267A>G		intron	N/A	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.724+4267A>G		intron	N/A	NP_001116079.1	Q01196-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.805+4267A>G		intron	N/A	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.805+4267A>G		intron	N/A	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.724+4267A>G		intron	N/A	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68817 AN: 151958 Hom.: 18633 Cov.: 31

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.489

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

GnomAD4 genome AF: 0.452 AC: 68810 AN: 152078 Hom.: 18629 Cov.: 31 AF XY: 0.455 AC XY: 33784 AN XY: 74318

African (AFR) AF: 0.146 AC: 6046 AN: 41516

American (AMR) AF: 0.433 AC: 6620 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2116 AN: 3468

East Asian (EAS) AF: 0.508 AC: 2622 AN: 5162

South Asian (SAS) AF: 0.580 AC: 2789 AN: 4810

European-Finnish (FIN) AF: 0.570 AC: 6012 AN: 10552

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.598 AC: 40634 AN: 67972

Other (OTH) AF: 0.485 AC: 1025 AN: 2112

Alfa AF: 0.533 Hom.: 49068

Bravo AF: 0.427

Asia WGS AF: 0.493 AC: 1715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0040
DANN	Benign	0.45
PhyloP100		-1.8

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

Other links and lift over

dbSNP: rs2243988; hg19: chr21-36202440;