21-34799412-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys) is a missense variant which is predicted to cause substitution of glutamine by lysine at amino acid 286. The highest population minor allele frequency in gnomAD v2 is 0.00003096 (4/129198 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). The germline variant has been reported in a patient with JMML but without features consistent with the RUNX1 phenotypic criteria (PMID:20955399), and the variant of unclear origin was reported in a patient with cytopenia (PMID:32241844). In vitro functional studies using HEK293T and HEL cells confirmed the expression of the mutant protein, and the variant demonstrated 80-115% transactivation activity for the CSF1R and MYL9 promoters (PMID:35026845) (BS3_Supporting). This aligns with the computational predictor, REVEL, which gives a score of 0.152 that is below the threshold of 0.50 and, thus, evidence that does not predict a damaging effect on RUNX1 function; the splice site predictor, SpliceAI, which gives a score of <0.20, also indicates that the variant has no impact on splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014280/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

1
6
12

Clinical Significance

Likely benign reviewed by expert panel U:3B:1

Conservation

PhyloP100: 9.17
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 Likely_benign. Variant got -2 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BS3
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.856C>A p.Gln286Lys missense_variant Exon 8 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.856C>A p.Gln286Lys missense_variant Exon 8 of 9 NM_001754.5 ENSP00000501943.1 Q01196-8

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251494
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135922
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000410
AC:
60
AN:
1461824
Hom.:
0
Cov.:
31
AF XY:
0.0000481
AC XY:
35
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000522
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:3Benign:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 14, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Q286K variant (also known as c.856C>A), located in coding exon 7 of the RUNX1 gene, results from a C to A substitution at nucleotide position 856. The glutamine at codon 286 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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 hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1
Jun 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 286 of the RUNX1 protein (p.Gln286Lys). This variant is present in population databases (rs769966051, gnomAD 0.004%). This missense change has been observed in individual(s) with juvenile myelomonocytic leukemia and neurofibromatosis type 1 (PMID: 20955399). ClinVar contains an entry for this variant (Variation ID: 575500). 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 with a negative predictive value of 80%. 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
Dec 12, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1
Sep 11, 2024
ClinGen Myeloid Malignancy Variant Curation Expert Panel
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys) is a missense variant which is predicted to cause substitution of glutamine by lysine at amino acid 286. The highest population minor allele frequency in gnomAD v2 is 0.00003096 (4/129198 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). The germline variant has been reported in a patient with JMML but without features consistent with the RUNX1 phenotypic criteria (PMID: 20955399), and the variant of unclear origin was reported in a patient with cytopenia (PMID: 32241844). In vitro functional studies using HEK293T and HEL cells confirmed the expression of the mutant protein, and the variant demonstrated 80-115% transactivation activity for the CSF1R and MYL9 promoters (PMID: 35026845) (BS3_Supporting). This aligns with the computational predictor, REVEL, which gives a score of 0.152 that is below the threshold of 0.50 and, thus, evidence that does not predict a damaging effect on RUNX1 function; the splice site predictor, SpliceAI, which gives a score of <0.20, also indicates that the variant has no impact on splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
T;.;.;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;.;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.41
T;T;T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
1.9
L;.;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.90
N;N;N;N
REVEL
Benign
0.15
Sift
Benign
0.18
T;T;T;T
Sift4G
Benign
0.64
T;T;T;T
Polyphen
0.44
B;B;B;.
Vest4
0.54
MVP
0.83
MPC
0.92
ClinPred
0.38
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.29
gMVP
0.35

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.

Other links and lift over

dbSNP: rs769966051; hg19: chr21-36171709; API