21-35539807-C-T

Variant names:

• chr21-35539807-C-T
• rs2223046
• ENST00000475045.6:c.-262+40853G>A

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-262+40853G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 151,950 control chromosomes in the GnomAD database, including 34,269 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 0.66 (34269 hom., cov: 30)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.490
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC100506403	NR_073512.1	n.105+40853G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000475045.6	c.-262+40853G>A		intron_variant	Intron 8 of 12	5		ENSP00000477072.1
RUNX1	ENST00000467692.5	n.101+40853G>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100920 AN: 151832 Hom.: 34240 Cov.: 30

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.654

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

GnomAD4 genome AF: 0.665 AC: 100996 AN: 151950 Hom.: 34269 Cov.: 30 AF XY: 0.666 AC XY: 49492 AN XY: 74270

African (AFR) AF: 0.806 AC: 33413 AN: 41430

American (AMR) AF: 0.630 AC: 9630 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2278 AN: 3466

East Asian (EAS) AF: 0.826 AC: 4252 AN: 5146

South Asian (SAS) AF: 0.701 AC: 3381 AN: 4822

European-Finnish (FIN) AF: 0.611 AC: 6452 AN: 10564

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

European-Non Finnish (NFE) AF: 0.582 AC: 39548 AN: 67932

Other (OTH) AF: 0.653 AC: 1378 AN: 2110

Alfa AF: 0.648 Hom.: 5650

Bravo AF: 0.674

Asia WGS AF: 0.784 AC: 2727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.73
DANN	Benign	0.70
PhyloP100		-0.49

Splicing

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

Other links and lift over

dbSNP: rs2223046; hg19: chr21-36912104;