chr21-34887095-A-G

Variant names:

• chr21-34887095-A-G
• rs762090330
• NM_001754.5:c.99T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.99T>C (p.Asp33=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI predicted acceptor loss of 0.32, which indicates it may impact splicing (BP4/BP7 not applied). 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: PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512319003/MONDO:0100083/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 splice_region, synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 4.83
• Publications: 3 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 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: 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.99T>C	p.Asp33Asp	splice_region synonymous	Exon 4 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.18T>C	p.Asp6Asp	synonymous	Exon 1 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.18T>C	p.Asp6Asp	synonymous	Exon 1 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.99T>C	p.Asp33Asp	splice_region synonymous	Exon 4 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.99T>C	p.Asp33Asp	splice_region synonymous	Exon 3 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.18T>C	p.Asp6Asp	synonymous	Exon 1 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Jul 25, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.99T>C (p.Asp33=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI predicted acceptor loss of 0.32, which indicates it may impact splicing (BP4/BP7 not applied). 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: PM2_supporting.

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Mar 10, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		4.8
PromoterAI		0.071	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762090330; hg19: chr21-36259392;