1-24902256-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004350.3(RUNX3):c.1114G>A(p.Ala372Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,587,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: RUNX3 NM_004350.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04329273).
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX3	NM_004350.3	c.1114G>A	p.Ala372Thr	missense_variant	5/5	ENST00000308873.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX3	ENST00000308873.11	c.1114G>A	p.Ala372Thr	missense_variant	5/5	1	NM_004350.3
RUNX3	ENST00000338888.4	c.1156G>A	p.Ala386Thr	missense_variant	7/7	1		P1
RUNX3	ENST00000399916.5	c.1156G>A	p.Ala386Thr	missense_variant	6/6	2		P1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000296 AC: 60 AN: 202494 Hom.: 0 AF XY: 0.000274 AC XY: 30 AN XY: 109456

Gnomad AFR exome AF: 0.0000820

Gnomad AMR exome AF: 0.0000351

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000176

Gnomad NFE exome AF: 0.000608

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000643 AC: 923 AN: 1435478 Hom.: 0 Cov.: 31 AF XY: 0.000616 AC XY: 438 AN XY: 711538

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.000182

Gnomad4 NFE exome AF: 0.000795

Gnomad4 OTH exome AF: 0.000554

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74368

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000586 AC: 5

ExAC AF: 0.000217 AC: 26

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

Jun 24, 2022

The c.1156G>A (p.A386T) 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 1156, causing the alanine (A) at amino acid position 386 to be replaced by a threonine (T). 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	0.066
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T;T;.
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	0.79	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.50	N;N;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.84	.;P;.
Vest4		0.043
MVP		0.60
MPC		0.73
ClinPred		0.044	T
GERP RS		3.2
Varity_R		0.058
gMVP		0.19

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: rs142303780; hg19: chr1-25228747; COSMIC: COSV99064162; COSMIC: COSV99064162;