rs202068364

Variant names:

• chr21-34792325-A-C
• rs202068364
• NM_001754.5:c.1253T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-34792325-A-C
• chr21-34792325-A-G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1253T>G (p.Met418Arg) is a variant which does not meet any ACMG/AMP criteria. 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: None. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014190/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 8.64
• Publications: 2 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 0 ACMG points.

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.1253T>G	p.Met418Arg	missense	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1172T>G	p.Met391Arg	missense	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.1253T>G	p.Met418Arg	missense	Exon 9 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.1253T>G	p.Met418Arg	missense	Exon 8 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.1172T>G	p.Met391Arg	missense	Exon 6 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 20 AN: 143740 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000248

Gnomad SAS AF: 0.000513

Gnomad FIN AF: 0.00106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000764

Gnomad OTH AF: 0.000495

GnomAD2 exomes AF: 0.0000572 AC: 9 AN: 157308 AF XY: 0.0000593

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: 0.0000744

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000451

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000799 AC: 990 AN: 1238320 Hom.: 0 Cov.: 36 AF XY: 0.000770 AC XY: 469 AN XY: 609258

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

African (AFR) AF: 0.00188 AC: 53 AN: 28128

American (AMR) AF: 0.00108 AC: 34 AN: 31592

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 48 AN: 20258

East Asian (EAS) AF: 0.00377 AC: 84 AN: 22278

South Asian (SAS) AF: 0.0000512 AC: 4 AN: 78140

European-Finnish (FIN) AF: 0.000964 AC: 31 AN: 32152

Middle Eastern (MID) AF: 0.00162 AC: 8 AN: 4926

European-Non Finnish (NFE) AF: 0.000672 AC: 654 AN: 972536

Other (OTH) AF: 0.00153 AC: 74 AN: 48310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000139 AC: 20 AN: 143894 Hom.: 0 Cov.: 31 AF XY: 0.0000713 AC XY: 5 AN XY: 70102

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

African (AFR) AF: 0.0000251 AC: 1 AN: 39888

American (AMR) AF: 0.00 AC: 0 AN: 14554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.000248 AC: 1 AN: 4036

South Asian (SAS) AF: 0.000510 AC: 2 AN: 3920

European-Finnish (FIN) AF: 0.00106 AC: 10 AN: 9436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000764 AC: 5 AN: 65476

Other (OTH) AF: 0.000489 AC: 1 AN: 2044

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000911580), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000988 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Aggressive systemic mastocytosis (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	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		0.86	P
Vest4		0.72
MVP		0.57
MPC		0.94
ClinPred		0.32	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94
Mutation Taster		=17/83	disease causing

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: rs202068364; hg19: chr21-36164622;