21-34792474-CATGCCG-CATGCCGATGCCG

Variant names:

• chr21-34792474-C-CATGCCG
• rs750495319
• NM_001754.5:c.1098_1103dupCGGCAT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The NM_001754.5(RUNX1):c.1098_1103dup (p.Ile366_Gly367dup) variant has a highest MAF 0.0001618 (11 out of 67990 alleles) in European (non-Finnish) subpopulation of gnomAD v3.1 (BS1). In summary, the clinical significance of this variant is Likely Benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CV239040/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: RUNX1 NM_001754.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3
• Conservation: PhyloP100: 6.14
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
• acute myeloid leukemia

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

ACMG classification

Specifications for RUNX1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.1098_1103dupCGGCAT	p.Ile366_Gly367dup	disruptive_inframe_insertion	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1017_1022dupCGGCAT	p.Ile339_Gly340dup	disruptive_inframe_insertion	Exon 6 of 6	NP_001001890.1	Q01196-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.1098_1103dupCGGCAT	p.Ile366_Gly367dup	disruptive_inframe_insertion	Exon 9 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.1098_1103dupCGGCAT	p.Ile366_Gly367dup	disruptive_inframe_insertion	Exon 8 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.1017_1022dupCGGCAT	p.Ile339_Gly340dup	disruptive_inframe_insertion	Exon 6 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000749 AC: 15 AN: 200284 AF XY: 0.0000924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000794 AC: 114 AN: 1435436 Hom.: 0 Cov.: 35 AF XY: 0.0000745 AC XY: 53 AN XY: 711532

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.0000740 AC: 3 AN: 40542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 38408

South Asian (SAS) AF: 0.0000605 AC: 5 AN: 82582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000901 AC: 99 AN: 1099100

Other (OTH) AF: 0.000118 AC: 7 AN: 59308

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74444

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000680

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	1	-	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

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

Other links and lift over

dbSNP: rs750495319; hg19: chr21-36164771;