rs769213771

Variant names:

• chr21-34887012-G-A
• rs769213771
• NM_001754.5:c.182C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34887012-G-A
• chr21-34887012-G-C
• chr21-34887012-G-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.182C>T (p.Pro61Leu) is a missense variant which has a REVEL score < 0.50 (0.385) and a SpliceAI score ≤ 0.20 (0.02) (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/CA10014573/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 3.77
• Publications: 13 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.182C>T	p.Pro61Leu	missense	Exon 4 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.101C>T	p.Pro34Leu	missense	Exon 1 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.101C>T	p.Pro34Leu	missense	Exon 1 of 5	NP_001116079.1	Q01196-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.182C>T	p.Pro61Leu	missense	Exon 4 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.182C>T	p.Pro61Leu	missense	Exon 3 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.101C>T	p.Pro34Leu	missense	Exon 1 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000217 AC: 5 AN: 230102 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000482

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000269 AC: 39 AN: 1450018 Hom.: 0 Cov.: 35 AF XY: 0.0000333 AC XY: 24 AN XY: 721306

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 85992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1109924

Other (OTH) AF: 0.0000166 AC: 1 AN: 60094

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia (1)
-	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
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.056
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.36	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.97	L
PhyloP100		3.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.023	D
Sift4G	Benign	0.19	T
Polyphen		0.96	D
Vest4		0.15
MutPred		0.11		Loss of loop (P = 0.0075)
MVP		0.92
MPC		0.80
ClinPred		0.73	D
GERP RS		3.0
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.35
Mutation Taster		=88/12	polymorphism

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: rs769213771; hg19: chr21-36259309; COSMIC: COSV104611427;