rs762247645

Variant names:

• chr21-34834604-A-G
• rs762247645
• NM_001754.5:c.614-3T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-34834604-A-G
• chr21-34834604-A-T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.614-3T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014391/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RUNX1 NM_001754.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004615
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 2.79
• 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: 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: Uncertain_significance. The variant received -1 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

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.614-3T>C		splice_region intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.533-3T>C		splice_region intron	N/A	NP_001001890.1
	RUNX1	NM_001122607.2		c.533-3T>C		splice_region intron	N/A	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.614-3T>C		splice_region intron	N/A	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.614-3T>C		splice_region intron	N/A	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.533-3T>C		splice_region intron	N/A	ENSP00000340690.4

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 5 AN: 140854 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000703

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000466

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248984 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000272 AC: 26 AN: 957306 Hom.: 0 Cov.: 32 AF XY: 0.0000246 AC XY: 12 AN XY: 487054

African (AFR) AF: 0.0000912 AC: 2 AN: 21932

American (AMR) AF: 0.0000260 AC: 1 AN: 38424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16930

East Asian (EAS) AF: 0.00 AC: 0 AN: 21042

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2918

European-Non Finnish (NFE) AF: 0.0000312 AC: 22 AN: 705624

Other (OTH) AF: 0.00 AC: 0 AN: 37086

GnomAD4 genome AF: 0.0000355 AC: 5 AN: 140854 Hom.: 0 Cov.: 30 AF XY: 0.0000293 AC XY: 2 AN XY: 68310

African (AFR) AF: 0.0000254 AC: 1 AN: 39300

American (AMR) AF: 0.0000703 AC: 1 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 4006

South Asian (SAS) AF: 0.00 AC: 0 AN: 3808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000466 AC: 3 AN: 64386

Other (OTH) AF: 0.00 AC: 0 AN: 1984

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.054
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: rs762247645; hg19: chr21-36206901;