21-34880598-G-T

Variant names:

• chr21-34880598-G-T
• rs267607026
• NM_001754.5:c.467C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PS4_Supporting PM2_Supporting PM1_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID:19357396, 27112265). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID:19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_Strong, PM2_supporting, PP3, PM1_Supporting, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248628/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.60
• Publications: 8 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.467C>A	p.Ala156Glu	missense	Exon 5 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.386C>A	p.Ala129Glu	missense	Exon 2 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.386C>A	p.Ala129Glu	missense	Exon 2 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.467C>A	p.Ala156Glu	missense	Exon 5 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.467C>A	p.Ala156Glu	missense	Exon 4 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.386C>A	p.Ala129Glu	missense	Exon 2 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Jun 24, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001754.4:c.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 19357396, 27112265). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_Strong, PM2_supporting, PP3, PM1_Supporting, PS4_Supporting.

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:1

May 28, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.78		Gain of solvent accessibility (P = 0.0145)
MVP		1.0
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		0.96
gMVP		0.98

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

Other links and lift over

dbSNP: rs267607026; hg19: chr21-36252895;