Genetic Variant RUNX3:p.Ala372Thr (chr1-24902256-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004350.3(RUNX3):c.1114G>A(p.Ala372Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,587,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

RUNX3
NM_004350.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04329273).

BS2

High AC in GnomAd4 at 57 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.1114G>A	p.Ala372Thr	missense	Exon 5 of 5	NP_004341.1	Q13761-1
RUNX3	NM_001031680.2		c.1156G>A	p.Ala386Thr	missense	Exon 6 of 6	NP_001026850.1	Q13761-2
RUNX3	NM_001320672.1		c.1156G>A	p.Ala386Thr	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.1114G>A	p.Ala372Thr	missense	Exon 5 of 5	ENSP00000308051.6	Q13761-1
RUNX3	ENST00000338888.4	TSL:1	c.1156G>A	p.Ala386Thr	missense	Exon 7 of 7	ENSP00000343477.3	Q13761-2
RUNX3	ENST00000399916.5	TSL:2	c.1156G>A	p.Ala386Thr	missense	Exon 6 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000296

AC:

AN:

202494

AF XY:

0.000274

show subpopulations

Gnomad AFR exome

AF:

0.0000820

Gnomad AMR exome

AF:

0.0000351

Gnomad ASJ exome

AF:

0.000112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000176

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000643

AC:

923

AN:

1435478

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

438

AN XY:

711538

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33326

American (AMR)

AF:

0.00

AC:

AN:

39380

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25530

East Asian (EAS)

AF:

0.00

AC:

AN:

38894

South Asian (SAS)

AF:

0.0000241

AC:

AN:

82878

European-Finnish (FIN)

AF:

0.000182

AC:

AN:

49532

Middle Eastern (MID)

AF:

0.000201

AC:

AN:

4980

European-Non Finnish (NFE)

AF:

0.000795

AC:

876

AN:

1101444

Other (OTH)

AF:

0.000554

AC:

AN:

59514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000374

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41448

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:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000586

AC:

ExAC

AF:

0.000217

AC:

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

0.066

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.21

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.043

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

-0.58

PhyloP100

1.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.50

REVEL

Benign

0.28

Sift

Benign

1.0

Sift4G

Benign

0.41

Polyphen

0.84

Vest4

0.043

MVP

0.60

MPC

0.73

ClinPred

0.044

GERP RS

3.2

Varity_R

0.058

gMVP

0.19

Mutation Taster

=79/21

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over