NM_004350.3:c.1114G>T

Variant names:

• chr1-24902256-C-A
• rs142303780
• NM_004350.3:c.1114G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004350.3(RUNX3):​c.1114G>T​(p.Ala372Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A372T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RUNX3 NM_004350.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09266719).

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.1114G>T	p.Ala372Ser	missense	Exon 5 of 5	NP_004341.1	Q13761-1
	RUNX3	NM_001031680.2		c.1156G>T	p.Ala386Ser	missense	Exon 6 of 6	NP_001026850.1	Q13761-2
	RUNX3	NM_001320672.1		c.1156G>T	p.Ala386Ser	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.1114G>T	p.Ala372Ser	missense	Exon 5 of 5	ENSP00000308051.6	Q13761-1
	RUNX3	ENST00000338888.4	TSL:1	c.1156G>T	p.Ala386Ser	missense	Exon 7 of 7	ENSP00000343477.3	Q13761-2
	RUNX3	ENST00000399916.5	TSL:2	c.1156G>T	p.Ala386Ser	missense	Exon 6 of 6	ENSP00000382800.1	Q13761-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435478 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711538

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 39380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25530

East Asian (EAS) AF: 0.00 AC: 0 AN: 38894

South Asian (SAS) AF: 0.00 AC: 0 AN: 82878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4980

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101444

Other (OTH) AF: 0.0000168 AC: 1 AN: 59514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	0.0083	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.11	N
PhyloP100		1.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.27
Sift	Benign	0.74	T
Sift4G	Benign	0.41	T
Polyphen		0.014	B
Vest4		0.037
MutPred		0.46		Gain of glycosylation at A372 (P = 0.0197)
MVP		0.43
MPC		0.68
ClinPred		0.41	T
GERP RS		3.2
Varity_R		0.076
gMVP		0.15
Mutation Taster		=91/9	polymorphism

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: rs142303780; hg19: chr1-25228747;