Genetic Variant RUNX1:p.Arg145Gly (chr21-34880632-T-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3PS3_ModeratePM2_SupportingPM1_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.433A>G (p.Arg145Gly) is a missense variant which has a REVEL score ≥ 0.88 (0.925) (PP3). Data from two or more secondary assays (FRET assay and SEUSS) demonstrate altered function, including decreased phosphorylation of RUNX1 and decreased gene expression (PS3_moderate; PMID:33692461, 32943879). This variant is located within the Runt Homology Domain (RHD; AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). 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: PS3_moderate, PP3, PM1_supporting, and PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616277/MONDO:0011071/008

Frequency

Genomes: not found (cov: 32)

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 1.54

Publications

7 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 links:

RUNX1-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

RUNX1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PS3

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

PM1

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX1	NM_001754.5	MANE Select	c.433A>G	p.Arg145Gly	missense	Exon 5 of 9	NP_001745.2
RUNX1	NM_001001890.3		c.352A>G	p.Arg118Gly	missense	Exon 2 of 6	NP_001001890.1	Q01196-1
RUNX1	NM_001122607.2		c.352A>G	p.Arg118Gly	missense	Exon 2 of 5	NP_001116079.1	Q01196-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.433A>G	p.Arg145Gly	missense	Exon 5 of 9	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.433A>G	p.Arg145Gly	missense	Exon 4 of 8	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000344691.8	TSL:1	c.352A>G	p.Arg118Gly	missense	Exon 2 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

PhyloP100

1.5

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MutPred

0.81

Loss of methylation at R118 (P = 0.0384)

MVP

0.99

MPC

1.8

ClinPred

0.99

GERP RS

4.1

Varity_R

0.98

gMVP

0.97

Mutation Taster

=16/84

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over