chr1-24902528-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004350.3(RUNX3):​c.842G>A​(p.Ser281Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RUNX3
NM_004350.3 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.33
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34393495).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RUNX3NM_004350.3 linkuse as main transcriptc.842G>A p.Ser281Asn missense_variant 5/5 ENST00000308873.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RUNX3ENST00000308873.11 linkuse as main transcriptc.842G>A p.Ser281Asn missense_variant 5/51 NM_004350.3 Q13761-1
RUNX3ENST00000338888.4 linkuse as main transcriptc.884G>A p.Ser295Asn missense_variant 7/71 P1Q13761-2
RUNX3ENST00000399916.5 linkuse as main transcriptc.884G>A p.Ser295Asn missense_variant 6/62 P1Q13761-2
RUNX3ENST00000496967.1 linkuse as main transcript downstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsJul 13, 2022The c.884G>A (p.S295N) 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 884, causing the serine (S) at amino acid position 295 to be replaced by an asparagine (N). 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
0.19
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
.;D;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.82
T;T;.
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.34
T;T;T
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Benign
1.7
.;L;.
MutationTaster
Benign
0.92
D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.7
N;N;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.057
T;T;T
Polyphen
0.36
.;B;.
Vest4
0.21
MutPred
0.35
.;Loss of glycosylation at S281 (P = 3e-04);.;
MVP
0.77
MPC
0.96
ClinPred
0.86
D
GERP RS
3.1
Varity_R
0.42
gMVP
0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-25229019; API