Variant 1-24902256-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 14/21 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX3	NM_004350.3 linkuse as main transcript	c.1114G>A	p.Ala372Thr	missense_variant	5/5	ENST00000308873.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX3	ENST00000308873.11 linkuse as main transcript	c.1114G>A	p.Ala372Thr	missense_variant	5/5	1	NM_004350.3		Q13761-1
RUNX3	ENST00000338888.4 linkuse as main transcript	c.1156G>A	p.Ala386Thr	missense_variant	7/7	1		P1	Q13761-2
RUNX3	ENST00000399916.5 linkuse as main transcript	c.1156G>A	p.Ala386Thr	missense_variant	6/6	2		P1	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

GnomAD3 exomes

AF:

0.000296

AC:

AN:

202494

Hom.:

AF XY:

0.000274

AC XY:

AN XY:

109456

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000241

Gnomad4 FIN exome

AF:

0.000182

Gnomad4 NFE exome

AF:

0.000795

Gnomad4 OTH exome

AF:

0.000554

GnomAD4 genome

AF:

0.000374

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000419

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.1156G>A (p.A386T) alteration is located in exon 6 (coding exon 6) of the RUNX3 gene. This alteration results from a G to A substitution at nucleotide position 1156, causing the alanine (A) at amino acid position 386 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

.;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.78

T;T;.

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

-0.58

.;N;.

MutationTaster

Benign

0.79

N;N;N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.50

N;N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.84

.;P;.

Vest4

0.043

MVP

0.60

MPC

0.73

ClinPred

0.044

GERP RS

3.2

Varity_R

0.058

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over