Variant rs749430925 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.65T>C (p.Ile22Thr) is a missense variant. This variant is present at a MAF of 0.00002915(0.002915%, 1/34310) in the Admixed American population of gnomAD v2.1.1. This missense variant has a REVEL score <0.50 (0.272)(BP4). No probands meeting RUNX1 FPDMM phenotypic criteria have been described with this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA410205770/MONDO:0011071/008

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 1.48

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]

RUNX1 links:

RUNX1 (HGNC:):

RUNX1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.65T>C	p.Ile22Thr	missense_variant	3/9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.65T>C	p.Ile22Thr	missense_variant	3/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249448

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134978

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1423760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710594

show subpopulations

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:

9.28e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2024

The p.I22T variant (also known as c.65T>C), located in coding exon 2 of the RUNX1 gene, results from a T to C substitution at nucleotide position 65. The isoleucine at codon 22 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Oct 29, 2024

NM_001754.5(RUNX1):c.65T>C (p.Ile22Thr) is a missense variant. This variant is present at a MAF of 0.00002915(0.002915%, 1/34310) in the Admixed American population of gnomAD v2.1.1. This missense variant has a REVEL score <0.50 (0.272)(BP4). No probands meeting RUNX1 FPDMM phenotypic criteria have been described with this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2022

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1471561). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 22 of the RUNX1 protein (p.Ile22Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.83

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.56

T;.;T;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

-0.10

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.22

N;N;.;N

REVEL

Benign

0.27

Sift

Benign

0.088

T;T;.;.

Sift4G

Uncertain

0.032

D;D;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.16

MutPred

0.29

Gain of disorder (P = 0.0374);Gain of disorder (P = 0.0374);Gain of disorder (P = 0.0374);Gain of disorder (P = 0.0374);

MVP

0.98

MPC

0.76

ClinPred

0.55

GERP RS

3.0

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over