Variant chr21-34792182-T-C 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.1396A>G (p.Met466Val) is a missense variant that has a REVEL score ≤0.50 (0.203) and SpliceAI is ≤0.20 (0.00) (BP4). 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: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014177/MONDO:0011071/008

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 2.86

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.1396A>G	p.Met466Val	missense_variant	9/9	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.1396A>G	p.Met466Val	missense_variant	9/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000147

AC:

AN:

135870

Hom.:

AF XY:

0.0000270

AC XY:

AN XY:

74036

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000378

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000363

AC:

AN:

1379136

Hom.:

Cov.:

AF XY:

0.00000440

AC XY:

AN XY:

681080

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:

0.00000464

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000181

AC:

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

Feb 16, 2021

This sequence change does not appear to have been previously described in patients with RUNX1-related disorders and been described in the gnomAD database with a low population frequency of 0.0015% (dbSNP rs762213305). The p.Met466Val change affects a moderately conserved amino acid residue located in a domain of the RUNX1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met466Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met466Val change remains unknown at this time. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28945609) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Nov 13, 2023

NM_001754.5(RUNX1):c.1396A>G (p.Met466Val) is a missense variant that has a REVEL score <=0.50 (0.203) and SpliceAI is <=0.20 (0.00) (BP4). 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: 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

May 17, 2023

ClinVar contains an entry for this variant (Variation ID: 1002421). 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. 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. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 466 of the RUNX1 protein (p.Met466Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;.;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D;.;D

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.0

M;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.25

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.84

P;D;D;.

Vest4

0.33

MutPred

0.76

Loss of glycosylation at S435 (P = 0.1306);.;.;.;

MVP

0.50

MPC

1.6

ClinPred

0.84

GERP RS

4.7

Varity_R

0.52

gMVP

0.45

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

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