rs766206710

Variant names:

• chr21-34887029-C-A
• rs766206710
• NM_001754.5:c.165G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34887029-C-A
• chr21-34887029-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BP7 PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.165G>T (p.Ala55=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.33)) (BP7). 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: BP4, BP7, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014579/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:2
• Conservation: PhyloP100: 1.34
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.165G>T	p.Ala55Ala	synonymous	Exon 4 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.84G>T	p.Ala28Ala	synonymous	Exon 1 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.84G>T	p.Ala28Ala	synonymous	Exon 1 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.165G>T	p.Ala55Ala	synonymous	Exon 4 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.165G>T	p.Ala55Ala	synonymous	Exon 3 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.84G>T	p.Ala28Ala	synonymous	Exon 1 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000432 AC: 1 AN: 231692 AF XY: 0.00000781

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.90e-7 AC: 1 AN: 1449128 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721240

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.0000224 AC: 1 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110930

Other (OTH) AF: 0.00 AC: 0 AN: 60152

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		1.3
PromoterAI		-0.021	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs766206710; hg19: chr21-36259326;