Genetic Variant RUNX3:p.Thr257Ala (chr1-24902601-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_004350.3(RUNX3):c.769A>G(p.Thr257Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RUNX3
NM_004350.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0910

Publications

1 publications found

Variant links:

Genes affected

RUNX3 (HGNC:10473): (RUNX family transcription factor 3) This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5'-PYGPYGGT-3' found in a number of enhancers and promoters, and can either activate or suppress transcription. It also interacts with other transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

RUNX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042936325).

BP6

Variant 1-24902601-T-C is Benign according to our data. Variant chr1-24902601-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2551878.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX3	NM_004350.3	MANE Select	c.769A>G	p.Thr257Ala	missense	Exon 5 of 5	NP_004341.1	Q13761-1
RUNX3	NM_001031680.2		c.811A>G	p.Thr271Ala	missense	Exon 6 of 6	NP_001026850.1	Q13761-2
RUNX3	NM_001320672.1		c.811A>G	p.Thr271Ala	missense	Exon 7 of 7	NP_001307601.1	Q13761-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX3	ENST00000308873.11	TSL:1 MANE Select	c.769A>G	p.Thr257Ala	missense	Exon 5 of 5	ENSP00000308051.6	Q13761-1
RUNX3	ENST00000338888.4	TSL:1	c.811A>G	p.Thr271Ala	missense	Exon 7 of 7	ENSP00000343477.3	Q13761-2
RUNX3	ENST00000399916.5	TSL:2	c.811A>G	p.Thr271Ala	missense	Exon 6 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.3

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.35

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.51

M_CAP

Benign

0.038

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

-0.091

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.31

REVEL

Benign

0.034

Sift

Benign

0.41

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.032

MutPred

0.16

Loss of phosphorylation at T257 (P = 0.0308)

MVP

0.44

MPC

0.72

ClinPred

0.044

GERP RS

-2.7

Varity_R

0.022

gMVP

0.18

Mutation Taster

=95/5

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

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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