chr21-34792164-G-GGC

Variant names:

• chr21-34792164-G-GGC
• rs1555884790
• NM_001754.5:c.1412_1413dupGC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001754.5(RUNX1):​c.1412_1413dupGC​(p.Leu472AlafsTer123) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R471R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 0.578
• Publications: 1 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-34792164-G-GGC is Pathogenic according to our data. Variant chr21-34792164-G-GGC is described in ClinVar as Pathogenic. ClinVar VariationId is 532664.Status of the report is reviewed_by_expert_panel, 3 stars.

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.1412_1413dupGC	p.Leu472AlafsTer123	frameshift	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1331_1332dupGC	p.Leu445AlafsTer123	frameshift	Exon 6 of 6	NP_001001890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.1412_1413dupGC	p.Leu472AlafsTer123	frameshift	Exon 9 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.1412_1413dupGC	p.Leu472AlafsTer123	frameshift	Exon 8 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.1331_1332dupGC	p.Leu445AlafsTer123	frameshift	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Jan 03, 2014

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Mar 26, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001754.4:c.1412_1413dup (p.Leu472Alafs) variant is a frameshift variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 472-480, including the VWRPY motif) is critical to protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 24353905). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 24353905). There is evidence of abnormal protein expression of this variant allele as a functional consequence of incorrect protein products (PS3_Moderate; PMID: 24353905). PS3_Moderate is applied because the variant meets PVS1_Strong. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PP1_strong, PS3_moderate, PM2_supporting, PS4_supporting, PM5_supporting.

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

Aug 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change inserts 2 nucleotides in exon 9 of the RUNX1 mRNA (c.1412_1413dupGC), causing a frameshift at codon 472.  While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids and to extend the RUNX1 protein beyond the natural translational stop signal by 114 amino acids (p.Leu472Alafs*123). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to segregate with familial platelet disorder with associated myeloid malignancy in a single family (PMID: 24353905, 26492932). Experimental studies have shown that this sequence change creates a stable RUNX1 protein that is visible by Western blot, however the functional consequences of this abnormal protein are unknown (PMID: 24353905). This variant disrupts the VWRPY motif (AAs 476-480) of the RUNX1 protein, which is required for binding to the transcriptional co-repressor Transducin-like enhancer of split (PMID: 9837750, 15749889). Although this motif is required for proper regulation of some RUNX1 target genes (PMID: 15749889, 14504086), deletion of this sequence does not significantly impact hematopoietic development or viability in mice (PMID: 14504086, 10594034). Therefore, the clinical significance of disrupting this domain is uncertain.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58

Splicing

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

Other links and lift over

dbSNP: rs1555884790; hg19: chr21-36164461;