rs1555889935

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5:c.770C>T (p.Thr257Ile) is a missense variant located in exon 7 of RUNX1. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410206725/MONDO:0011071/008

Frequency

Genomes: not found (cov: 31)

Consequence

RUNX1
NM_001754.5 missense

Scores

4
11
4

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 7.79
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RUNX1NM_001754.5 linkc.770C>T p.Thr257Ile missense_variant Exon 7 of 9 ENST00000675419.1 NP_001745.2 Q01196-8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RUNX1ENST00000675419.1 linkc.770C>T p.Thr257Ile missense_variant Exon 7 of 9 NM_001754.5 ENSP00000501943.1 Q01196-8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Uncertain:1
Aug 01, 2024
ClinGen Myeloid Malignancy Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

NM_001754.5:c.770C>T (p.Thr257Ile) is a missense variant located in exon 7 of RUNX1. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1
Nov 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 257 of the RUNX1 protein (p.Thr257Ile). 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: 464007). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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
0.19
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;.;.;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;.;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Uncertain
0.72
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
2.0
M;.;.;M;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-2.6
D;D;D;D;D
REVEL
Uncertain
0.60
Sift
Uncertain
0.012
D;D;D;T;T
Sift4G
Benign
0.097
T;T;T;T;.
Polyphen
0.95
P;P;P;D;.
Vest4
0.64
MutPred
0.24
Loss of glycosylation at T230 (P = 0.018);.;.;Loss of glycosylation at T230 (P = 0.018);.;
MVP
0.99
MPC
1.2
ClinPred
0.93
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555889935; hg19: chr21-36206742; API