Genetic Variant RUNX3:p.Ile18Asn (chr1-24964519-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001031680.2(RUNX3):c.53T>A(p.Ile18Asn) variant causes a missense change. The variant allele was found at a frequency of 0.504 in 1,608,192 control chromosomes in the GnomAD database, including 208,979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.50 ( 19749 hom., cov: 32)

Exomes 𝑓: 0.50 ( 189230 hom. )

Consequence

RUNX3
NM_001031680.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.82

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:

RUNX3-AS1 (HGNC:40513): (RUNX3 antisense RNA 1)

RUNX3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6813297E-5).

BP6

Variant 1-24964519-A-T is Benign according to our data. Variant chr1-24964519-A-T is described in ClinVar as [Benign]. Clinvar id is 2688533.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
RUNX3	NM_001031680.2 link	c.53T>A	p.Ile18Asn	missense_variant	Exon 1 of 6	NP_001026850.1	Q13761-2A0A024RAH4
RUNX3	NM_001320672.1 link	c.53T>A	p.Ile18Asn	missense_variant	Exon 2 of 7	NP_001307601.1	Q13761-2A0A024RAH4
RUNX3	XM_005246024.5 link	c.53T>A	p.Ile18Asn	missense_variant	Exon 2 of 7	XP_005246081.1	Q13761-2A0A024RAH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
RUNX3	ENST00000338888.4 link	c.53T>A	p.Ile18Asn	missense_variant	Exon 2 of 7	1	ENSP00000343477.3	Q13761-2
RUNX3	ENST00000479341.1 link	n.163T>A		non_coding_transcript_exon_variant	Exon 2 of 3	1
RUNX3	ENST00000399916.5 link	c.53T>A	p.Ile18Asn	missense_variant	Exon 1 of 6	2	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes

AF:

0.503

AC:

76330

AN:

151844

Hom.:

19720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.425

Gnomad AMI

AF:

0.651

Gnomad AMR

AF:

0.647

Gnomad ASJ

AF:

0.504

Gnomad EAS

AF:

0.709

Gnomad SAS

AF:

0.669

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.482

Gnomad OTH

AF:

0.533

GnomAD3 exomes

AF:

0.560

AC:

135790

AN:

242600

Hom.:

39767

AF XY:

0.559

AC XY:

73333

AN XY:

131286

show subpopulations

Gnomad AFR exome

AF:

0.421

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.505

Gnomad EAS exome

AF:

0.711

Gnomad SAS exome

AF:

0.674

Gnomad FIN exome

AF:

0.533

Gnomad NFE exome

AF:

0.475

Gnomad OTH exome

AF:

0.542

GnomAD4 exome

AF:

0.504

AC:

734217

AN:

1456230

Hom.:

189230

Cov.:

AF XY:

0.508

AC XY:

368166

AN XY:

724028

show subpopulations

Gnomad4 AFR exome

AF:

0.421

Gnomad4 AMR exome

AF:

0.740

Gnomad4 ASJ exome

AF:

0.508

Gnomad4 EAS exome

AF:

0.659

Gnomad4 SAS exome

AF:

0.667

Gnomad4 FIN exome

AF:

0.526

Gnomad4 NFE exome

AF:

0.477

Gnomad4 OTH exome

AF:

0.521

GnomAD4 genome

AF:

0.503

AC:

76384

AN:

151962

Hom.:

19749

Cov.:

AF XY:

0.515

AC XY:

38268

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.425

Gnomad4 AMR

AF:

0.647

Gnomad4 ASJ

AF:

0.504

Gnomad4 EAS

AF:

0.709

Gnomad4 SAS

AF:

0.669

Gnomad4 FIN

AF:

0.536

Gnomad4 NFE

AF:

0.482

Gnomad4 OTH

AF:

0.538

Alfa

AF:

0.494

Hom.:

6071

Bravo

AF:

0.509

TwinsUK

AF:

0.481

AC:

1785

ALSPAC

AF:

0.456

AC:

1757

ESP6500AA

AF:

0.424

AC:

1866

ESP6500EA

AF:

0.484

AC:

4162

ExAC

AF:

0.543

AC:

65816

Asia WGS

AF:

0.694

AC:

2414

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 76. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.97

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

T;.

MetaRNN

Benign

0.000017

T;T

MetaSVM

Benign

-0.90

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.26

T;T

Polyphen

1.0

D;D

Vest4

0.36

MPC

2.1

ClinPred

0.051

GERP RS

5.7

gMVP

0.30

Splicing

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