21-34809752-G-C

Variant names:

• chr21-34809752-G-C
• rs2268277
• NM_001754.5:c.806-10290C>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.806-10290C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 151,838 control chromosomes in the GnomAD database, including 12,669 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 0.40 (12669 hom., cov: 31)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.476
• 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: 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.806-10290C>G		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.806-10290C>G		intron_variant	Intron 7 of 8		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61071 AN: 151720 Hom.: 12646 Cov.: 31

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.389

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

GnomAD4 genome AF: 0.403 AC: 61147 AN: 151838 Hom.: 12669 Cov.: 31 AF XY: 0.401 AC XY: 29750 AN XY: 74200

African (AFR) AF: 0.500 AC: 20715 AN: 41394

American (AMR) AF: 0.412 AC: 6282 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1511 AN: 3466

East Asian (EAS) AF: 0.375 AC: 1930 AN: 5140

South Asian (SAS) AF: 0.381 AC: 1832 AN: 4814

European-Finnish (FIN) AF: 0.341 AC: 3587 AN: 10520

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24196 AN: 67942

Other (OTH) AF: 0.392 AC: 824 AN: 2104

Alfa AF: 0.217 Hom.: 443

Bravo AF: 0.412

Asia WGS AF: 0.410 AC: 1424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.6
DANN	Benign	0.81
PhyloP100		-0.48

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: rs2268277; hg19: chr21-36182049;