21-34792381-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1197C>G (p.Ser399Arg) is a missense mutation that is not present in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has a REVEL score < 0.50 (0.126), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410147801/MONDO:0011071/008

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 2.89

Publications

0 publications found

Variant links:

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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

RUNX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.1197C>G	p.Ser399Arg	missense_variant	Exon 9 of 9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.1197C>G	p.Ser399Arg	missense_variant	Exon 9 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1414370

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

699038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32668

American (AMR)

AF:

0.0000271

AC:

AN:

36918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

37450

South Asian (SAS)

AF:

0.00

AC:

AN:

80562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1087614

Other (OTH)

AF:

0.00

AC:

AN:

58598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S399R variant (also known as c.1197C>G), located in coding exon 8 of the RUNX1 gene, results from a C to G substitution at nucleotide position 1197. The serine at codon 399 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Jul 17, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.5(RUNX1):c.1197C>G (p.Ser399Arg) is a missense mutation that is not present in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has a REVEL score < 0.50 (0.126), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

May 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 399 of the RUNX1 protein (p.Ser399Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;.

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;.;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

2.9

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.5

D;N;N;D

REVEL

Benign

0.13

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Benign

0.087

T;T;T;T

Polyphen

0.88

P;B;B;.

Vest4

0.55

MutPred

0.53

Loss of glycosylation at S372 (P = 0.0183);.;.;.;

MVP

0.48

MPC

0.78

ClinPred

0.89

GERP RS

2.2

Varity_R

0.39

gMVP

0.44

Mutation Taster

=70/30

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over