21-34787885-G-A

Variant names:

• chr21-34787885-G-A
• rs186103543
• NM_001754.5:c.*4250C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP2

This summary comes from the ClinGen Evidence Repository: The c.*4250C>T variant in the 3' UTR has an MAF of 0.002009 (0.2%, 31/15430 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10644601/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (0 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 4.54
• Publications: 0 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 -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.*4250C>T		3_prime_UTR	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.*4250C>T		3_prime_UTR	Exon 6 of 6	NP_001001890.1	Q01196-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.*4250C>T		3_prime_UTR	Exon 9 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.*4250C>T		3_prime_UTR	Exon 8 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.*4250C>T		3_prime_UTR	Exon 6 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000951 AC: 77 AN: 80970 Hom.: 0 Cov.: 0 AF XY: 0.00105 AC XY: 39 AN XY: 37216

African (AFR) AF: 0.000514 AC: 2 AN: 3894

American (AMR) AF: 0.00 AC: 0 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5124

East Asian (EAS) AF: 0.00 AC: 0 AN: 11406

South Asian (SAS) AF: 0.00 AC: 0 AN: 702

European-Finnish (FIN) AF: 0.0172 AC: 1 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.00142 AC: 71 AN: 50038

Other (OTH) AF: 0.000444 AC: 3 AN: 6762

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74498

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.000691

ClinVar

ClinVar submissions

Significance: Benign

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		4.5

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: rs186103543; hg19: chr21-36160182;