rs74315450

Positions:

• chr21-34859485-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP1 PP3 PS4 PS3

This summary comes from the ClinGen Evidence Repository: Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID:17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID:27112265, 28748566, 10508512). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID:27112265, 28748566, 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, PS4, PM1, PM2, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248610/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.90

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-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.602G>A	p.Arg201Gln	missense_variant	6/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.602G>A	p.Arg201Gln	missense_variant	6/9		NM_001754.5	A1
RUNX1-AS1	ENST00000651798.1	n.661+22539C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460892 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726878

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene, and are associated with acute myeloid leukaemia (MIM#601626) and familial platelet disorder with associated myeloid malignancy (MIM#601399) (PMID: 28179279). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated runt domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic by the ClinGen Myeloid Malignancy Variant Curation Expert Panel (ClinVar). It has been reported in multiple individuals with myelodysplastic syndrome or thrombocytopenia (PMIDs: 27112265, 28748566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Jul 30, 2019	Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBF-beta binding and sub-cellular localization (PS3; PMID: 17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID: 27112265, 28748566, 10508512). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID: 27112265, 28748566, 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, PS4, PM1, PM2, PP1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 201 of the RUNX1 protein (p.Arg201Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of platelet dysfunction, mild to moderate thrombocytopenia, and myeloid malignancies (PMID: 10508512, 21725049, 27112265). It has also been observed to segregate with disease in related individuals. This variant is also known as R174Q. ClinVar contains an entry for this variant (Variation ID: 14464). 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 expected to disrupt RUNX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 11830488, 21725049, 22898599, 25490895). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.047	D;D;D;T;T;T
Sift4G	Uncertain	0.057	T;T;T;T;T;.
Polyphen		1.0	D;P;P;.;D;.
Vest4		0.95
MutPred		0.78		Loss of MoRF binding (P = 0.019);.;.;Loss of MoRF binding (P = 0.019);Loss of MoRF binding (P = 0.019);.;
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.86

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

Other links and lift over

dbSNP: rs74315450; hg19: chr21-36231782; COSMIC: COSV55867719; COSMIC: COSV55867719;