chr21-34808717-G-A

Variant names:

• chr21-34808717-G-A
• rs2268276
• NM_001754.5:c.806-9255C>T

Variant summary

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

The NM_001754.5(RUNX1):​c.806-9255C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 152,010 control chromosomes in the GnomAD database, including 11,818 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 0.38 (11818 hom., cov: 31)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.157
• 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: 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=-0.54).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.446 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.806-9255C>T		intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.725-9255C>T		intron	N/A	NP_001001890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.806-9255C>T		intron	N/A	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.806-9255C>T		intron	N/A	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.725-9255C>T		intron	N/A	ENSP00000340690.4

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57731 AN: 151892 Hom.: 11822 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.397

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

GnomAD4 genome AF: 0.380 AC: 57743 AN: 152010 Hom.: 11818 Cov.: 31 AF XY: 0.380 AC XY: 28231 AN XY: 74294

African (AFR) AF: 0.227 AC: 9410 AN: 41452

American (AMR) AF: 0.431 AC: 6586 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1528 AN: 3468

East Asian (EAS) AF: 0.374 AC: 1927 AN: 5152

South Asian (SAS) AF: 0.442 AC: 2133 AN: 4822

European-Finnish (FIN) AF: 0.397 AC: 4192 AN: 10560

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30597 AN: 67978

Other (OTH) AF: 0.399 AC: 842 AN: 2110

Alfa AF: 0.419 Hom.: 2781

Bravo AF: 0.378

Asia WGS AF: 0.409 AC: 1421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.6
DANN	Benign	0.83
PhyloP100		0.16

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: rs2268276; hg19: chr21-36181014; COSMIC: COSV55878822;