21-35538367-A-G

Variant names:

• chr21-35538367-A-G
• rs1040328
• ENST00000475045.6:c.-262+42293T>C

Variant summary

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

The ENST00000467692.5(RUNX1):​n.101+42293T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 152,176 control chromosomes in the GnomAD database, including 34,874 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 0.67 (34874 hom., cov: 33)
• Consequence: RUNX1 ENST00000467692.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.642
• Publications: 5 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

LOC100506403 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOC100506403	NR_073512.1		n.105+42293T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000475045.6	TSL:5	c.-262+42293T>C		intron	N/A	ENSP00000477072.1
	RUNX1	ENST00000467692.5	TSL:2	n.101+42293T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101762 AN: 152058 Hom.: 34840 Cov.: 33

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.656

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

GnomAD4 genome AF: 0.669 AC: 101845 AN: 152176 Hom.: 34874 Cov.: 33 AF XY: 0.671 AC XY: 49892 AN XY: 74386

African (AFR) AF: 0.819 AC: 34024 AN: 41542

American (AMR) AF: 0.634 AC: 9683 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2321 AN: 3470

East Asian (EAS) AF: 0.826 AC: 4274 AN: 5176

South Asian (SAS) AF: 0.702 AC: 3384 AN: 4822

European-Finnish (FIN) AF: 0.611 AC: 6462 AN: 10568

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39648 AN: 67996

Other (OTH) AF: 0.655 AC: 1387 AN: 2116

Alfa AF: 0.656 Hom.: 5876

Bravo AF: 0.679

Asia WGS AF: 0.787 AC: 2738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.7
DANN	Benign	0.56
PhyloP100		0.64

Splicing

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

Other links and lift over

dbSNP: rs1040328; hg19: chr21-36910664;