Genetic Variant RUNX3:p.Ile18Ser (chr1-24964519-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001031680.2(RUNX3):c.53T>G(p.Ile18Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,388 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. I18N) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RUNX3
NM_001031680.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.82

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:

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

RUNX3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39227727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031680.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX3	NM_001031680.2	c.53T>G	p.Ile18Ser	missense	Exon 1 of 6	NP_001026850.1	Q13761-2
RUNX3	NM_001320672.1	c.53T>G	p.Ile18Ser	missense	Exon 2 of 7	NP_001307601.1	Q13761-2
RUNX3-AS1	NR_183339.1	n.3838A>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX3	ENST00000338888.4	TSL:1	c.53T>G	p.Ile18Ser	missense	Exon 2 of 7	ENSP00000343477.3	Q13761-2
RUNX3	ENST00000479341.1	TSL:1	n.163T>G		non_coding_transcript_exon	Exon 2 of 3
RUNX3	ENST00000399916.5	TSL:2	c.53T>G	p.Ile18Ser	missense	Exon 1 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724602

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39508

South Asian (SAS)

AF:

0.00

AC:

AN:

85352

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109790

Other (OTH)

AF:

0.00

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.49

PhyloP100

5.8

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.46

Sift

Uncertain

0.015

Sift4G

Benign

0.41

Polyphen

1.0

Vest4

0.41

MutPred

0.34

Gain of glycosylation at I18 (P = 0.0076)

MVP

0.69

MPC

1.8

ClinPred

0.96

GERP RS

5.7

PromoterAI

-0.040

Neutral

(source)

gMVP

0.42

Mutation Taster

=68/32

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over