1-24902486-G-C

Variant names:

• chr1-24902486-G-C
• NM_004350.3:c.884C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004350.3(RUNX3):​c.884C>G​(p.Ala295Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. A295V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RUNX3 NM_004350.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23494422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX3	NM_004350.3	c.884C>G	p.Ala295Gly	missense_variant	Exon 5 of 5	ENST00000308873.11	NP_004341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX3	ENST00000308873.11	c.884C>G	p.Ala295Gly	missense_variant	Exon 5 of 5	1	NM_004350.3	ENSP00000308051.6
RUNX3	ENST00000338888.4	c.926C>G	p.Ala309Gly	missense_variant	Exon 7 of 7	1		ENSP00000343477.3
RUNX3	ENST00000399916.5	c.926C>G	p.Ala309Gly	missense_variant	Exon 6 of 6	2		ENSP00000382800.1
RUNX3	ENST00000496967.1	n.*86C>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448158 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000763

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.3	.;L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.070	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.33	.;B;.
Vest4		0.14
MutPred		0.32		.;Loss of stability (P = 0.1035);.;
MVP		0.69
MPC		0.79
ClinPred		0.59	D
GERP RS		3.2
Varity_R		0.11
gMVP		0.096

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: chr1-25228977;