21-34880568-C-T

Position:

• chr21-34880568-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PP1 PM2_Supporting PS3 PS4_Moderate PM6_Supporting PM1

This summary comes from the ClinGen Evidence Repository: Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.497G>A (p.Arg166Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID:11830488, 25840971, 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID:10508512, 28960434, 26175287). This variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.962) (PP3). There are two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID:8960434, 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID:10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PS4_Moderate, PM2_supporting, PP3, PM6_Supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616941/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.57

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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	c.497G>A	p.Arg166Gln	missense_variant	5/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.497G>A	p.Arg166Gln	missense_variant	5/9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 166 of the RUNX1 protein (p.Arg166Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia, myelodysplastic syndrome and/or acute myeloid leukemia (PMID: 10508512, 26175287, 27210295, 28960434). It has also been observed to segregate with disease in related individuals. This variant is also known as c.416G>A. ClinVar contains an entry for this variant (Variation ID: 417961). 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 have shown that this missense change affects RUNX1 function (PMID: 11830488, 22012064, 23848403, 25840971, 26916619, 31048839). This variant disrupts the p.Arg166 amino acid residue in RUNX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11049997, 12002768, 22318203, 25840971). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Inherited bleeding disorder, platelet-type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Oct 04, 2019

- -

RUNX1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The RUNX1 c.497G>A variant is predicted to result in the amino acid substitution p.Arg166Gln. This variant is a highly curated, known pathogenic variant that is associated with RUNX1-mediated disease and predisposition for MDS / AML (for details see https://www.ncbi.nlm.nih.gov/clinvar/variation/417961/; Luo et al. 2019. PubMed ID: 31648317). This variant is not present in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 10, 2024

PP1, PP3, PP4, PP5, PM1_supporting, PM2, PM6, PS3, PS4_moderate -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Sep 10, 2024

Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.497G>A (p.Arg166Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 10508512, 28960434, 26175287). This variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.962) (PP3). There are two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 8960434, 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PS4_Moderate, PM2_supporting, PP3, PM6_Supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;.;.;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.97
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs1060499616; hg19: chr21-36252865; COSMIC: COSV55867644; COSMIC: COSV55867644;