NM_001754.5:c.619C>T

Variant names:

• chr21-34834596-G-A
• rs1555890007
• NM_001754.5:c.619C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.619C>T (p.Arg207Trp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.8109, PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000436615.1). 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: PS4_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410207207/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 5.87
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.619C>T	p.Arg207Trp	missense	Exon 7 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.538C>T	p.Arg180Trp	missense	Exon 4 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.538C>T	p.Arg180Trp	missense	Exon 4 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.619C>T	p.Arg207Trp	missense	Exon 7 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.619C>T	p.Arg207Trp	missense	Exon 6 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.538C>T	p.Arg180Trp	missense	Exon 4 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149684 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1288804 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 640224

African (AFR) AF: 0.00 AC: 0 AN: 28384

American (AMR) AF: 0.00 AC: 0 AN: 39752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20114

East Asian (EAS) AF: 0.00 AC: 0 AN: 26276

South Asian (SAS) AF: 0.00 AC: 0 AN: 84528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1000472

Other (OTH) AF: 0.00 AC: 0 AN: 49014

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149684 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73026

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40978

American (AMR) AF: 0.00 AC: 0 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4938

South Asian (SAS) AF: 0.00 AC: 0 AN: 4534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10092

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67354

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)
-	1	-	Acute myeloid leukemia (1)
-	1	-	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.72
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.64
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555890007; hg19: chr21-36206893; COSMIC: COSV55897170;