rs2834680

Variant names:

• chr21-34937166-T-C
• rs2834680
• NM_001754.5:c.59-44203A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001754.5(RUNX1):​c.59-44203A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 152,270 control chromosomes in the GnomAD database, including 82 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 0.024 (82 hom., cov: 31)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.763
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0237 (3606/152270) while in subpopulation NFE AF = 0.0382 (2598/68016). AF 95% confidence interval is 0.037. There are 82 homozygotes in GnomAd4. There are 1672 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3606 AD gene.

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.59-44203A>G		intron	N/A	NP_001745.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.59-44203A>G		intron	N/A	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.59-44203A>G		intron	N/A	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000416754.1	TSL:1	c.59-44203A>G		intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3605 AN: 152152 Hom.: 81 Cov.: 31

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0306

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

GnomAD4 genome AF: 0.0237 AC: 3606 AN: 152270 Hom.: 82 Cov.: 31 AF XY: 0.0225 AC XY: 1672 AN XY: 74454

African (AFR) AF: 0.00602 AC: 250 AN: 41554

American (AMR) AF: 0.0201 AC: 307 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0319 AC: 154 AN: 4826

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0382 AC: 2598 AN: 68016

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0347 Hom.: 304

Bravo AF: 0.0238

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		0.76

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: rs2834680; hg19: chr21-36309463;