rs771529157

Variant names:

• chr21-34792348-C-T
• rs771529157
• NM_001754.5:c.1230G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP7 BP4

This summary comes from the ClinGen Evidence Repository: This synonymous variant has SpliceAI ∆ scores ≤ 0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -2.375) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014191/MONDO:0100083/008

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:5
• Conservation: PhyloP100: -2.36
• Publications: 2 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 -2 ACMG points.

• 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.1230G>A	p.Ser410Ser	synonymous	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1149G>A	p.Ser383Ser	synonymous	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.1230G>A	p.Ser410Ser	synonymous	Exon 9 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.1230G>A	p.Ser410Ser	synonymous	Exon 8 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.1149G>A	p.Ser383Ser	synonymous	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151600 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 160662 AF XY: 0.0000234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000315

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 22 AN: 1404940 Hom.: 0 Cov.: 35 AF XY: 0.0000202 AC XY: 14 AN XY: 693888

African (AFR) AF: 0.00 AC: 0 AN: 32196

American (AMR) AF: 0.00 AC: 0 AN: 36022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 36746

South Asian (SAS) AF: 0.00 AC: 0 AN: 79872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48322

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5686

European-Non Finnish (NFE) AF: 0.0000148 AC: 16 AN: 1082742

Other (OTH) AF: 0.0000687 AC: 4 AN: 58224

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151600 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74030

African (AFR) AF: 0.00 AC: 0 AN: 41276

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.9
DANN	Benign	0.88
PhyloP100		-2.4

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: rs771529157; hg19: chr21-36164645;