chr1-24902171-G-A

Position:

• chr1-24902171-G-A

Variant summary

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

The NM_004350.3(RUNX3):​c.1199C>T​(p.Ala400Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000282 in 1,419,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (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: 5.11

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=0.1346327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX3	NM_004350.3	c.1199C>T	p.Ala400Val	missense_variant	5/5	ENST00000308873.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX3	ENST00000308873.11	c.1199C>T	p.Ala400Val	missense_variant	5/5	1	NM_004350.3
RUNX3	ENST00000338888.4	c.1241C>T	p.Ala414Val	missense_variant	7/7	1		P1
RUNX3	ENST00000399916.5	c.1241C>T	p.Ala414Val	missense_variant	6/6	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1419488 Hom.: 0 Cov.: 31 AF XY: 0.00000427 AC XY: 3 AN XY: 702194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.1241C>T (p.A414V) alteration is located in exon 6 (coding exon 6) of the RUNX3 gene. This alteration results from a C to T substitution at nucleotide position 1241, causing the alanine (A) at amino acid position 414 to be replaced by a valine (V). 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	0.099
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.22	.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.81	.;P;.
Vest4		0.063
MutPred		0.70		.;Loss of relative solvent accessibility (P = 0.114);.;
MVP		0.40
MPC		1.4
ClinPred		0.85	D
GERP RS		3.2
Varity_R		0.083
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs1476523757; hg19: chr1-25228662;