rs2834643

Variant names:

• chr21-34814099-A-G
• rs2834643
• NM_001754.5:c.806-14637T>C

Variant summary

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

The NM_001754.5(RUNX1):​c.806-14637T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,032 control chromosomes in the GnomAD database, including 13,579 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 0.42 (13579 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.449
• Publications: 6 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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.806-14637T>C		intron_variant	Intron 7 of 8	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.806-14637T>C		intron_variant	Intron 7 of 8		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64055 AN: 151914 Hom.: 13570 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.422 AC: 64113 AN: 152032 Hom.: 13579 Cov.: 32 AF XY: 0.421 AC XY: 31323 AN XY: 74314

African (AFR) AF: 0.433 AC: 17937 AN: 41456

American (AMR) AF: 0.431 AC: 6579 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1631 AN: 3466

East Asian (EAS) AF: 0.382 AC: 1980 AN: 5184

South Asian (SAS) AF: 0.404 AC: 1943 AN: 4814

European-Finnish (FIN) AF: 0.406 AC: 4285 AN: 10558

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28524 AN: 67958

Other (OTH) AF: 0.414 AC: 876 AN: 2114

Alfa AF: 0.426 Hom.: 5421

Bravo AF: 0.424

Asia WGS AF: 0.419 AC: 1460 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.53
PhyloP100		-0.45

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: rs2834643; hg19: chr21-36186396;