rs1555899861

Positions:

• chr21-34887038-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001754.5(RUNX1):​c.156G>A​(p.Met52Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. M52K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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 4 ACMG points.

• PM1: In a domain Runt (size 128) in uniprot entity RUNX1_HUMAN there are 24 pathogenic changes around while only 6 benign (80%) in NM_001754.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.156G>A	p.Met52Ile	missense_variant	4/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.156G>A	p.Met52Ile	missense_variant	4/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 25, 2017

This sequence change replaces methionine with isoleucine at codon 52 of the RUNX1 protein (p.Met52Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RUNX1-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.4	N;D;D;N;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D;D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;.;D
Polyphen		0.94	P;D;D;.;B;.;.
Vest4		0.44
MutPred		0.23		Gain of methylation at K24 (P = 0.0239);.;.;Gain of methylation at K24 (P = 0.0239);Gain of methylation at K24 (P = 0.0239);.;.;
MVP		0.98
MPC		1.7
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.66

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: rs1555899861; hg19: chr21-36259335;