rs1555884790

chr21-34792164-G-GGCchr21-34792164-GGC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001754.5(RUNX1):c.1413_1414insGC(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 (★★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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. Fraction of 0.0208 CDS is truncated, and there are 1 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 id is 532664.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.1413_1414insGC	p.Leu472AlafsTer123	frameshift_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.1413_1414insGC	p.Leu472AlafsTer123	frameshift_variant	9/9		NM_001754.5	A1

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

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

Pathogenic, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Jul 26, 2019	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). 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, PS4_supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 12, 2017	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. 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. 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 has been reported to segregate with familial platelet disorder with associated myeloid malignancy in a single family (PMID: 24353905, 26492932). 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 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). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2014

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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: rs1555884790; hg19: chr21-36164461;