Genetic Variant RUNX3:p.Thr365Ile (chr1-24902276-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004350.3(RUNX3):c.1094C>T(p.Thr365Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000152 in 1,444,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T365S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RUNX3
NM_004350.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.35

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2625411).

BS2

High AC in GnomAdExome4 at 22 AD gene.

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.1094C>T	p.Thr365Ile	missense	Exon 5 of 5	NP_004341.1	Q13761-1
RUNX3	NM_001031680.2		c.1136C>T	p.Thr379Ile	missense	Exon 6 of 6	NP_001026850.1	Q13761-2
RUNX3	NM_001320672.1		c.1136C>T	p.Thr379Ile	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.1094C>T	p.Thr365Ile	missense	Exon 5 of 5	ENSP00000308051.6	Q13761-1
RUNX3	ENST00000338888.4	TSL:1	c.1136C>T	p.Thr379Ile	missense	Exon 7 of 7	ENSP00000343477.3	Q13761-2
RUNX3	ENST00000399916.5	TSL:2	c.1136C>T	p.Thr379Ile	missense	Exon 6 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000463

AC:

AN:

216158

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000627

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1444616

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

717188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

41334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25658

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39120

South Asian (SAS)

AF:

0.00

AC:

AN:

84016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5242

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1106100

Other (OTH)

AF:

0.0000167

AC:

AN:

59778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

M_CAP

Benign

0.033

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.9

PhyloP100

6.4

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.15

Sift

Uncertain

0.0010

Sift4G

Benign

0.076

Polyphen

0.88

Vest4

0.11

MutPred

0.40

Loss of glycosylation at T365 (P = 0.0311)

MVP

0.27

MPC

1.3

ClinPred

0.97

GERP RS

4.2

Varity_R

0.55

gMVP

0.25

Mutation Taster

=64/36

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over