rs1017287894

chr21-34792496-G-Cchr21-34792496-G-A

Variant summary

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

The NM_001754.5(RUNX1):c.1082C>G(p.Thr361Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,574 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T361I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 3.99

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.19871032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.1082C>G	p.Thr361Ser	missense_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.1082C>G	p.Thr361Ser	missense_variant	9/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444574 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 716892

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jul 07, 2022

The NM_001754.5(RUNX1):c.1082C>G (p.Thr361Ser) variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Multiple lines of computational evidence suggest no impact on gene or gene product (REVEL score is ≤ 0.50 (0.031) and no splice effect predicted (0.00 ≤0.20)(BP4). In summary, this variant meets the criteria to be classified as a VUS. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 15, 2023

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 361 of the RUNX1 protein (p.Thr361Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 463976). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.60	N;.;.;.
MutationTaster	Benign	0.62	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.18
MutPred		0.42		Gain of loop (P = 0.0097);.;.;.;
MVP		0.79
MPC		0.55
ClinPred		0.49	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.31

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: rs1017287894; hg19: chr21-36164793;