chr21-34922045-C-T

Variant names:

• chr21-34922045-C-T
• rs2834676
• NM_001754.5:c.59-29082G>A

Variant summary

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

The NM_001754.5(RUNX1):​c.59-29082G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,082 control chromosomes in the GnomAD database, including 10,891 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 0.35 (10891 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.193
• Publications: 4 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 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.59-29082G>A		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.59-29082G>A		intron	N/A	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.59-29082G>A		intron	N/A	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000416754.1	TSL:1	c.59-29082G>A		intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52749 AN: 151964 Hom.: 10884 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.347 AC: 52768 AN: 152082 Hom.: 10891 Cov.: 32 AF XY: 0.354 AC XY: 26298 AN XY: 74352

African (AFR) AF: 0.121 AC: 5042 AN: 41502

American (AMR) AF: 0.322 AC: 4928 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1314 AN: 3472

East Asian (EAS) AF: 0.555 AC: 2860 AN: 5156

South Asian (SAS) AF: 0.420 AC: 2023 AN: 4818

European-Finnish (FIN) AF: 0.530 AC: 5596 AN: 10560

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29845 AN: 67972

Other (OTH) AF: 0.363 AC: 766 AN: 2108

Alfa AF: 0.407 Hom.: 58585

Bravo AF: 0.321

Asia WGS AF: 0.417 AC: 1449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.67
PhyloP100		0.19

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: rs2834676; hg19: chr21-36294342;