NM_001754.5:c.1389C>G

Variant names:

• chr21-34792189-G-C
• rs61750222
• NM_001754.5:c.1389C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP7 BP4 BP2 BA1

This summary comes from the ClinGen Evidence Repository: NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) is a synonymous variant which has a minor allele frequency of 0.1206 (1976/16382 alleles) in the African subpopulation of the gnomAD cohort, meeting the threshold for BA1. It is detected in a homozygous state in 202 individuals in gnomAD (BP2). Splicing predictors SSF and MES indicate no significant impact on the canonical splice site, and no cryptic splice sites are created (BP4). Evolutionary conservation algorithms predict the site as not being conserved (BP7). 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, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014178/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.045 (356 hom., cov: 31)
  • Exomes 𝑓: 0.016 (552 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -0.485
• Publications: 6 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 -11 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.1389C>G	p.Pro463Pro	synonymous	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1308C>G	p.Pro436Pro	synonymous	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.1389C>G	p.Pro463Pro	synonymous	Exon 9 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.1389C>G	p.Pro463Pro	synonymous	Exon 8 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.1308C>G	p.Pro436Pro	synonymous	Exon 6 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6873 AN: 151862 Hom.: 349 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.000853

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00925

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0311 AC: 4309 AN: 138592 AF XY: 0.0283

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0552

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.0216

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00925

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0157 AC: 21791 AN: 1384492 Hom.: 552 Cov.: 33 AF XY: 0.0156 AC XY: 10686 AN XY: 683826

African (AFR) AF: 0.128 AC: 4048 AN: 31624

American (AMR) AF: 0.0537 AC: 1962 AN: 36512

Ashkenazi Jewish (ASJ) AF: 0.0606 AC: 1499 AN: 24740

East Asian (EAS) AF: 0.0227 AC: 823 AN: 36290

South Asian (SAS) AF: 0.0292 AC: 2299 AN: 78646

European-Finnish (FIN) AF: 0.00203 AC: 69 AN: 33932

Middle Eastern (MID) AF: 0.0266 AC: 127 AN: 4770

European-Non Finnish (NFE) AF: 0.00891 AC: 9621 AN: 1080252

Other (OTH) AF: 0.0233 AC: 1343 AN: 57726

GnomAD4 genome AF: 0.0454 AC: 6906 AN: 151978 Hom.: 356 Cov.: 31 AF XY: 0.0444 AC XY: 3301 AN XY: 74302

African (AFR) AF: 0.121 AC: 5024 AN: 41486

American (AMR) AF: 0.0455 AC: 696 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.0249 AC: 128 AN: 5144

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4822

European-Finnish (FIN) AF: 0.000853 AC: 9 AN: 10556

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00925 AC: 628 AN: 67904

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0162 Hom.: 12

Bravo AF: 0.0519

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Acute myeloid leukemia (1)
-	-	1	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.2
DANN	Benign	0.75
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: rs61750222; hg19: chr21-36164486;