rs1555894743

Positions:

• chr21-34859554-G-GTGA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.530_532dup (p.Ile177_Thr178insIle) is an in-frame insertion which affects a residue within the Runt Homology domain (AA 89-294) but does not impact a residue which has been established as a hotspot (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). 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, PM4_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616526/MONDO:0100083/008

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUNX1 NM_001754.5 inframe_insertion
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 8.01

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.532_533insTCA	p.Ile177dup	inframe_insertion	6/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.532_533insTCA	p.Ile177dup	inframe_insertion	6/9		NM_001754.5	ENSP00000501943	A1
RUNX1-AS1	ENST00000651798.1	n.661+22611_661+22613dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 03, 2016	In summary, this variant is a novel sequence change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RUNX1-related disease. This sequence change duplicates 3 nucleotides in exon 6 of the RUNX1 mRNA (c.530_532dupTCA). This leads to the duplication of 1 amino acid residue in the RUNX1 protein (p.Ile177dup) but otherwise preserves the integrity of the reading frame. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Sep 25, 2024	NM_001754.5(RUNX1):c.530_532dup (p.Ile177_Thr178insIle) is an in-frame insertion which affects a residue within the Runt Homology domain (AA 89-294) but does not impact a residue which has been established as a hotspot (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). 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, PM4_supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555894743; hg19: chr21-36231851;