chr21-35428765-T-C

Variant names:

• chr21-35428765-T-C
• rs4817723
• ENST00000475045.6:c.-197+33196A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000467692.5(RUNX1):​n.166+33196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 152,100 control chromosomes in the GnomAD database, including 54,719 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.84 (54719 hom., cov: 30)
• Consequence: RUNX1 ENST00000467692.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.258
• 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 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

LOC100506403 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000467692.5. 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
	LOC100506403	NR_073512.1		n.170+33196A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000475045.6	TSL:5	c.-197+33196A>G		intron	N/A	ENSP00000477072.1	V9GYT5
	RUNX1	ENST00000467692.5	TSL:2	n.166+33196A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128330 AN: 151984 Hom.: 54680 Cov.: 30

Gnomad AFR AF: 0.964

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.822

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.854

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.844 AC: 128423 AN: 152100 Hom.: 54719 Cov.: 30 AF XY: 0.839 AC XY: 62396 AN XY: 74352

African (AFR) AF: 0.964 AC: 40036 AN: 41526

American (AMR) AF: 0.822 AC: 12561 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2892 AN: 3470

East Asian (EAS) AF: 0.796 AC: 4094 AN: 5142

South Asian (SAS) AF: 0.835 AC: 4017 AN: 4810

European-Finnish (FIN) AF: 0.732 AC: 7733 AN: 10568

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54324 AN: 67978

Other (OTH) AF: 0.854 AC: 1803 AN: 2112

Alfa AF: 0.756 Hom.: 2462

Bravo AF: 0.855

Asia WGS AF: 0.829 AC: 2884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.6
DANN	Benign	0.52
PhyloP100		-0.26

Splicing

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

Other links and lift over

dbSNP: rs4817723; hg19: chr21-36801063;