1-24902456-T-C

Variant names:

• chr1-24902456-T-C
• rs773403827
• NM_004350.3:c.914A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004350.3(RUNX3):​c.914A>G​(p.His305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,602,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RUNX3 NM_004350.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07
• Publications: 0 publications found

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

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=0.41686746).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX3	NM_004350.3	MANE Select	c.914A>G	p.His305Arg	missense	Exon 5 of 5	NP_004341.1	Q13761-1
	RUNX3	NM_001031680.2		c.956A>G	p.His319Arg	missense	Exon 6 of 6	NP_001026850.1	Q13761-2
	RUNX3	NM_001320672.1		c.956A>G	p.His319Arg	missense	Exon 7 of 7	NP_001307601.1	Q13761-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX3	ENST00000308873.11	TSL:1 MANE Select	c.914A>G	p.His305Arg	missense	Exon 5 of 5	ENSP00000308051.6	Q13761-1
	RUNX3	ENST00000338888.4	TSL:1	c.956A>G	p.His319Arg	missense	Exon 7 of 7	ENSP00000343477.3	Q13761-2
	RUNX3	ENST00000399916.5	TSL:2	c.956A>G	p.His319Arg	missense	Exon 6 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247380 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450440 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719168

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1103268

Other (OTH) AF: 0.00 AC: 0 AN: 59784

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000224 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.040
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.25	T
Polyphen		0.79	P
Vest4		0.57
MutPred		0.33		Gain of MoRF binding (P = 0.0584)
MVP		0.84
MPC		1.7
ClinPred		0.85	D
GERP RS		1.6
Varity_R		0.39
gMVP		0.83
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs773403827; hg19: chr1-25228947;