Genetic Variant NM_004350.3:c.1148G>A (chr1-24902222-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004350.3(RUNX3):c.1148G>A(p.Gly383Asp) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G383S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RUNX3
NM_004350.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15422273).

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.1148G>A	p.Gly383Asp	missense	Exon 5 of 5	NP_004341.1	Q13761-1
RUNX3	NM_001031680.2		c.1190G>A	p.Gly397Asp	missense	Exon 6 of 6	NP_001026850.1	Q13761-2
RUNX3	NM_001320672.1		c.1190G>A	p.Gly397Asp	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.1148G>A	p.Gly383Asp	missense	Exon 5 of 5	ENSP00000308051.6	Q13761-1
RUNX3	ENST00000338888.4	TSL:1	c.1190G>A	p.Gly397Asp	missense	Exon 7 of 7	ENSP00000343477.3	Q13761-2
RUNX3	ENST00000399916.5	TSL:2	c.1190G>A	p.Gly397Asp	missense	Exon 6 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1419742

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702414

African (AFR)

AF:

0.00

AC:

AN:

33012

American (AMR)

AF:

0.00

AC:

AN:

37514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25330

East Asian (EAS)

AF:

0.00

AC:

AN:

38212

South Asian (SAS)

AF:

0.00

AC:

AN:

81320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4642

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092578

Other (OTH)

AF:

0.00

AC:

AN:

58840

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.29

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.0028

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0092

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.35

REVEL

Benign

0.068

Sift

Benign

0.041

Sift4G

Benign

0.43

Polyphen

0.56

Vest4

0.078

MutPred

0.41

Loss of catalytic residue at G383 (P = 0.012)

MVP

0.35

MPC

1.4

ClinPred

0.43

GERP RS

2.6

Varity_R

0.094

gMVP

0.20

Mutation Taster

=80/20

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