chr21-34880553-GT-G

Variant names:

• chr21-34880553-GT-G
• rs587776810
• NM_001754.5:c.508+3delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PS4_Supporting PM2_Supporting PS3 PP1_Strong

This summary comes from the ClinGen Evidence Repository: There is RT-PCR assay evidence demonstrating that the NM_001754.4:c.508+3delA variant creates a cryptic splice donor site that is used and results in a frameshift and introduction of premature termination codon (PS3; PMID:11830488). This variant was found to co-segregate with disease in multiple affected family members, with eight meioses observed in one family (PP1_Strong; PMID:11830488). It is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant (in intron 5) is located in reference to the exon at positions +3 for donor splice site and has a predicted decrease in the score of the canonical splice site by at least 75% (measured by both MES and SSF). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID:11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM2_supporting, PP3, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248618/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUNX1 NM_001754.5 splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 1.20
• 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-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.508+3delA		splice_region intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.427+3delA		splice_region intron	N/A	NP_001001890.1
	RUNX1	NM_001122607.2		c.427+3delA		splice_region intron	N/A	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.508+3delA		splice_region intron	N/A	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.508+3delA		splice_region intron	N/A	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.427+3delA		splice_region intron	N/A	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)
1	-	-	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 27
DS_DL_spliceai		0.99		Position offset: 4

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

Other links and lift over

dbSNP: rs587776810; hg19: chr21-36252850;