NM_001754.5:c.205G>A

Variant names:

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.205G>A (p.Gly69Ser) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.0.00001470 (1/68046 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.439) and SpliceAI score is ≤ 0.20 (0) (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/CA320642805/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 3.65

Publications

13 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 -1 ACMG points.

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.205G>A	p.Gly69Ser	missense_variant	Exon 4 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.205G>A	p.Gly69Ser	missense_variant	Exon 4 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1454678

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

86042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110232

Other (OTH)

AF:

0.00

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G69S variant (also known as c.205G>A), located in coding exon 3 of the RUNX1 gene, results from a G to A substitution at nucleotide position 205. The glycine at codon 69 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Apr 19, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Nov 13, 2023

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.5(RUNX1):c.205G>A (p.Gly69Ser) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.0.00001470 (1/68046 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.439) and SpliceAI score is <= 0.20 (0) (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. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Jul 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 69 of the RUNX1 protein (p.Gly69Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 948058). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

D;.;.;.;.;.;T

Eigen

Benign

0.074

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D;.;D;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.34

T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.4

L;.;.;.;L;.;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.3

N;N;N;N;N;N;D

REVEL

Uncertain

0.44

Sift

Benign

0.24

T;T;T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T;.;T

Polyphen

0.98

D;B;B;.;D;.;.

Vest4

0.12

MutPred

0.18

Gain of helix (P = 0.0199);.;.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;.;

MVP

0.96

MPC

0.73

ClinPred

0.83

GERP RS

4.1

PromoterAI

0.00080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.61

Mutation Taster

=53/47

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