Variant rs1555890007 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PS4_SupportingPM2_SupportingPP3

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.619C>T (p.Arg207Trp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.8109, PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000436615.1). 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: PS4_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410207207/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 5.87

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PS4

PM2

PP3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.619C>T	p.Arg207Trp	missense_variant	7/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.619C>T	p.Arg207Trp	missense_variant	7/9		NM_001754.5	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1288804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

640224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73026

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 13, 2017

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jul 11, 2024

NM_001754.5(RUNX1):c.619C>T (p.Arg207Trp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.8109, PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000436615.1). 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: PS4_supporting, PM2_supporting, PP3. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2023

This missense change has been observed in individual(s) with acute myleoid leukemia and thromobocytopenia (PMID: 31309983, 32315381). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 207 of the RUNX1 protein (p.Arg207Trp). This variant is not present in population databases (gnomAD no frequency). This variant is also known as c.538C>T (p.Arg180Trp). ClinVar contains an entry for this variant (Variation ID: 436615). 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) has been performed at Invitae 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RUNX1 function (PMID: 33692461). 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. -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.5

D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.72

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.9

Varity_R

0.63

gMVP

0.64

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.

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